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Salimbeni, Simona. "Déficience en TDP1 et instabilité génomique dans les cellules non-réplicatives." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30065.
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L'ataxie spinocérébelleuse avec neuropathie axonale (SCAN1) est un rare syndrome neurodégénératif récessif associé à une atrophie cérébelleuse et à une neuropathie périphérique. Il est causé par une mutation homozygote dans le gène tyrosyl-ADN phosphodiestérase-1 (TDP1) (A1478G). Cette mutation entraîne une substitution de l'histidine 493 par une arginine (H493R) dans le site catalytique de TDP1, ce qui conduit à une diminution de l’activité de TDP1. TDP1 hydrolyse la liaison entre une extrémité 3' de l'ADN et une tyrosine au sein d'un complexe de clivage de la topoisomérase I (TOP1cc) piégé sur la chromatine. TDP1 n'excise pas seulement les TOP1cc piégés, mais répare également d'autres lésions bloquant l'extrémité 3', notamment les 3'-phosphoglycolates qui résultent d’une oxydation. Toutefois, le mécanisme par lequel la mutation TDP1 H493R entraine le phénotype SCAN1, qui est associé avec la mort des neurones post-mitotiques, est peu connu. Les cassures double-brin (DSBs) de l'ADN sont peu fréquentes mais parmi les lésions génomiques les plus sévères. Un défaut de réparation peut induire la mort cellulaire, et elles ont été impliquées dans la pathogénèse de nombreuses maladies humaines, incluant des syndromes neurodégénératifs. Mon objectif de doctorat a été de déterminer si le phénotype SCAN1 pouvait être lié à une accumulation de DSBs dans des cellules non réplicatives portant la mutation TDP1 H493R. Les seuls modèles disponibles pour étudier l'impact de cette mutation étaient des lignées de cellules lymphoblastoïdes provenant de patients SCAN1 comparées à celles d'individus sains. Nous avons donc généré des modèles de cellules d'ostéosarcome U2OS homozygotes pour TDP1 H493R ou TDP1 KO en utilisant la technique CRISPR-Cas9. Nous avons également généré des cellules primaires de poumon WI38 hTERT TDP1 KO. Nous avons observé que les cellules TDP1 H493R et TDP1 KO accumulent des DSBs endogènes, principalement dans la phase G1 du cycle cellulaire par rapport à la phase S. Une augmentation de DSBs a également été observée après déplétion de TDP1 par siRNA dans les cellules WI38 hTERT quiescentes, suggérant la nature réplication-indépendante de ces DSBs. Le traitement des cellules TDP1 H493R et TDP1 KO par la camptothécine, qui induit spécifiquement des TOP1ccs, suggère en outre que l'accumulation de DSBs pourrait être liée au défaut d'élimination des TOP1ccs. Ensuite, nous nous sommes demandé si l'accumulation de DSBs dans ces cellules pouvait être liée à une augmentation de la production de ces DSBs et/ou à un défaut dans leur réparation. Notamment, les structures R-loops qui se forment lors de la transcription peuvent induire des DSBs dans les cellules non réplicatives. Nous avons montré que la déficience en TDP1 modulait les R-loops sur certains gènes, ce qui soulève la possibilité de leur implication dans la formation de DSBs. L'analyse de la réparation des DSBs après traitement par la camptothécine a révélé que les cellules TDP1 H493R et TDP1 KO étaient toutes deux défectueuses dans la réparation des DSBs en G1 mais pas en S, la mutation TDP1 H493R ayant l'effet le plus prononcé. Ces résultats suggèrent que les DSBs pourraient s'accumuler spécifiquement dans les cellules déficientes en TDP1 qui ne répliquent pas en raison d'une réparation défectueuse de ces cassures. L’ensemble des notre résultats apporte de nouvelles informations sur l'étiologie du syndrome neurodégénératif SCAN1. Ce travail a été soutenu par une bourse de doctorat dans le cadre du programme universitaire franco-italien VINCI 2016Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a rare recessive neurodegenerative syndrome associated with cerebellar atrophy and peripheral neuropathy. It is caused by a homozygous missense mutation in the tyrosyl-DNA phosphodiesterase-1 (TDP1) gene (A1478G). This results in a substitution of histidine for arginine-493 (H493R) in the TDP1 catalytic site, leading to a reduced TDP1 activity. TDP1 hydrolyses the bond between a DNA 3’-end and a tyrosyl moiety within a trapped topoisomerase I cleavage complex (TOP1cc). TDP1 not only excises trapped TOP1ccs but also processes other 3’-end-blocking lesions, including 3’-phosphoglycolates that result from oxidation. Even so, how TDP1 H493R mutation promotes the SCAN1 phenotype, which is associated with the death of post-mitotic neurons, is unclear. DNA double-strand breaks (DSBs) are infrequent but among the most harmful genomic lesions. Their defective repair can induce cell death, and they have been implicated in the pathogenesis of several human diseases, including neurodegenerative syndromes. Hence, my Ph.D. objective was to investigate whether the SCAN1 phenotype could be related to an accumulation of DSBs in non-replicating cells harboring the H493R mutation of TDP1. The only available models to study the impact of TDP1 H493R mutation were lymphoblastoid cell lines derived from SCAN1 patients compared to those of healthy individuals. Hence, we have generated models of osteosarcoma U2OS cells homozygous for TDP1 H493R or TDP1 KO employing the CRISPR-Cas9 technique. We have also generated primary lung WI38 hTERT fibroblasts TDP1 KO. We found that both TDP1 H493R and TDP1 KO cells accumulate endogenous DSBs, primarily in the G1 phase of the cell cycle compared to S phase. A similar increase of DSBs was observed in quiescent WI38 hTERT cells following depletion of TDP1 with siRNA, suggesting the replication-independent nature of DSBs. Treatment of TDP1 H493R and TDP1 KO cells with camptothecin to induced trapped TOP1ccs, further suggests that accumulation of DSBs could be related to the defective removal of TOP1ccs. Next, we asked whether DSB accumulation in those cells could be related to an increase in DSB production and/or a defect in their repair. Notably, R-loop structures that form co-transcriptionally can induce DSBs in non-replicating cells. We found that TDP1 deficiency modulated R-loop levels at some gene loci, raising the possibility of their implication in DSB formation. Analysis of DSB repair following camptothecin treatment revealed that both TDP1 H493R and TDP1 KO cells were defective in the repair of DSBs in G1 but not in S, with TDP1 H493R having the most pronounced effect. These results suggest that DSBs would accumulate specifically in TDP1-deficient cells that do not undergo replication, due to a defective repair of those breaks. Together, our results provide insights on the etiology of the SCAN1 neurodegenerative syndrome. This work was supported by a PhD fellowship under the French-Italian University VINCI Program 2016
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Vuillaume, Isabelle. "Identification d'un nouveau locus responsable d'une ataxie spinocérébelleuse héréditaire (SCA21) : approche gène-candidat." Lille 2, 2003. http://www.theses.fr/2003LIL2MT27.
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Kelp, Alexandra [Verfasser]. "Generierung und Charakterisierung eines transgenen Rattenmodells der Spinozerebellären Ataxie Typ 17 (SCA17) / Alexandra Kelp." München : Verlag Dr. Hut, 2015. http://d-nb.info/1075409616/34.
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Schuster, Stefanie [Verfasser]. "Deciphering the effect of mutant STUB1 on the heat shock response in SCAR16 patient-derived cells / Stefanie Schuster." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1216501882/34.
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Öhlund, Rebecca. "Könsskillnader i välbefinnande utifrån val av fysisk aktivitet." Thesis, Örebro universitet, Institutionen för juridik, psykologi och socialt arbete, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-43343.
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Samhället uppmuntrar individer att se över sina hälsovanor för att öka välbefinnandet. Syftet var att undersöka om val av fysisk aktivitet hade effekt på den generella hälsan i ökat subjektivt välbefinnande samt om det fanns könsskillnader i dessa. Sextio män och kvinnor mellan 25-50 år valdes slumpmässigt ut från träningsanläggningar för att besvara the 12-item General Health Questionnaire (GHQ-12) samt Swedish Core Affect Scale (SCAS). Resultatet visade på signifikant ökning av välbefinnande efter fysisk aktivitet samt inga könsskillnader. Dock fanns en signifikant interaktionseffekt mellan kön och fysisk aktivitet, de män som promenerade och kvinnor som konditionstränade hade högst välbefinnande och generell hälsa. Slutsatsen blev att välbefinnandet ökade oavsett kön efter fysisk aktivitet dock gav olika aktiviteter varierande ökningar mellan könen.The society encourages individuals to promote their health habits in order to improve their well-being. The aim was to investigate the effect of different types of physical activity on experience of general health in well-being in men and woman. Sixty men and women in ages 25-50 years old were randomly chosen from training facilities to answer the 12-item General Health Questionnaire (GHQ-12) and Swedish Core Affect Scale (SCAS). The results showed a significant increase in positive well-being due to the practice of physical activity, but there were no gender difference. However, it was found a significant interaction effect of age and physical activity on health, the men who walked and women who conditioning trained showed highest well-being and general health. The conclusion was that the well-being increase regardless of sex after physical activity, however, different activities gave varying increases between the sexes.
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Bampi, Giovana Bavia. "Estudo de haplótipos em famílias com ataxia espinocerebelar tipo 10(SCA10) : evidências de um efeito fundador da mutação." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/119618.
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A ataxia espinocerebelar tipo 10 (SCA10) é uma doença neurodegenerativa rara de herança autossômica dominante caracterizada por atrofia cerebelar com alterações da marcha e, em alguns casos, convulsões. A SCA10 é causada por expansões de repetições pentanucleotídicas ATTCT no íntron 9 do gene ATXN10, o qual se localiza no locus 22q13. Alelos normais apresentam entre 10 a 29 repetições e o alelo patogênico apresenta entre 800 a 4.500 repetições. Até o momento, casos de SCA10 foram descritos apenas em pacientes miscigenados de países do continente americano como México, Brasil, Argentina, Venezuela, Colômbia, Estados Unidos e, mais recentemente, Peru. A origem ameríndia auto declarada pelos pacientes com SCA10 e a ausência de casos em países europeus e asiáticos indicam a hipótese de ocorrência de um efeito fundador da mutação nas populações nativas americanas. O objetivo deste trabalho foi investigar a hipótese de origem ancestral comum da mutação no gene ATXN10. As amostras analisadas foram proveniente de 16 famílias brasileiras e de 21 famílias peruanas com SCA10. Além do grupo de pacientes, um grupo controle composto por 48 indivíduos saudáveis da população indígena Quechua do Peru foi também incluída na análise assim como 51 controles brasileiros de um estudo anterior. Os resultados obtidos mostraram que o haplótipo 19CGGC14 associado ao alelo da expansão está presente em 46,8% das famílias de brasileiros e 62,8% das famílias de peruanos. As frequências de ambos os grupos não é estatisticamente diferente dos controles Quechua (57,3%), sendo diferente dos controles brasileiros (11,8%) (p<0,001). Entretanto, origem etnogeográfica da mutação ainda é desconhecida. O haplótipo comum mínimo foi expandido incluindo outros dois marcadores polimórficos, os quais integram dois haplótipos com alta prevalência em populações nativo americanas com o intuito de obter uma aproximação da origem da região cromossômica onde a mutação está inserida. Dois haplótipos mais frequentes 19-13-CGGC-14-10 e 19- 15-CGGC-14-10 foram identificados nos controles indígenas Quechua, com frequências relativas de 14,3% e 13,3% respectivamente. O segundo haplótipo mais frequente em Quechuas, 19-15-CGGC-14-10, é encontrado em 50,0% das famílias brasileiras e em 64,7% das famílias Peruanas com SCA10. Esses achados corroboram a hipótese de origem ameríndia da mutação.Spinocerebellar ataxia type 10 is a rare autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and epilepsy in some cases. The disease is caused by a pentanucleotide ATTCT expansion in intron 9 of the ATXN10 gene, which is located at locus 22q13.3. Normal alleles range from 10 to 29 repeats while mutant allele range from 800 to 4,500 repeats. SCA10 has only been described so far in admixed patients from American countries such as Mexico, Brazil, Argentina, Venezuela, Colombia, United States and more recently Peru. The self-declared Amerindian ancestry by patients and the absence of SCA10 in European and Asian countries leads to the hypothesis of a mutation founder effect in the Native American populations. The aim of this study was to investigate the hypothesis of a common ancestral origin of ATXN10 mutation. Samples analyzed were from 16 Brazilian families, 21 Peruvian families with SCA10. In addition to patient samples, 48 healthy individuals of Indigenous Quechua from Peru were also included in the laboratorial analyses along with 51 Brazilian controls from a previous study. Our data has shown that 19CGGC14-shared haplotype was found in 46.8% of Brazilian and in 62.8% of Peruvian families. Frequencies from both groups are not statistically different from Quechua controls (57.3%), but they are statistically different from Brazilian controls (11.8%) (p<0.001). However, the mutation ethno-geographical origin remains unclear. The minimal common haplotype was expanded by including two additional polymorphic markers that are found at high prevalence in two haplotypes in Native American populations aiming to shed light on the chromosome region ancestry where the mutation arose. Two frequent haplotypes, 19-13-CGGC-14-10 and 19-15- CGGC-14-10 were identified in Indigenous Quechua controls, with relative frequencies of 14.3% and 13.3% respectively. The second most frequent haplotype in Quechuas, 19-15- CGGC-14-10, is found in 50.0% of Brazilian and in 64.7% of Peruvian families with SCA10. These findings corroborate the hypothesis of a Native American ancestry of the mutation.
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Tang, Matthew Y. "Gene reprogramming by K48R mutant ubiquitin in a mouse model of SCA1." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/27054.
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Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease resulting from the loss of Purkinje neurons within the cerebellum. The causative agent of the disease is the expansion of a trinucleotide repeat in its gene product ataxin-1. The ubiquitin proteasome pathway (UPP) has been implicated in SCA1 but the role of proteolysis in the disease is still poorly understood. To further investigate this issue in vivo , genetic crosses were performed between a well established mouse model of SCA1 and novel strains expressing elevated levels of wild type or mutant isoforms of ubiquitin. The K48R mutant isoform of ubiquitin (a dominant negative inhibitor of proteolysis) was found to significantly delay the deterioration of Purkinje neurons as evidenced by behavioral, morphological, and molecular indicators. This delay was accompanied by the restoration of genes involved in calcium and glutamate signalling and by the stabilization of postsynaptic density proteins whose abundance/activity would otherwise decline in the course of the SCA1 disease. These results are consistent with transcriptional dysregulation as a key mechanism in neurodegeneration and suggest that the UPP is a useful target for the development of novel therapies.
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Keiser, Megan Kathryn. "Gene therapies for spinocerebellar ataxia type 1." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/2540.
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Spinocerebellar ataxia type 1 (SCA1) is an adult onset, autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in ataxin-1, which encodes the ataxin-1 protein. SCA1 is one of nine polyQ-expansion gain-of-function diseases which includes Huntington's disease, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and other ataxias. Clinical symptoms of SCA1 include ataxia, dysarthria, ophthalmoparesis, muscle wasting, and extrapyramidal and bulbar dysfunction. Cerebellar Purkinje cells (PCs), neurons in the inferior olive and nuclei of the brainstem are affected. No disease-modifying therapy exists for SCA1. The goals of my thesis were to assess the safety and efficacy of AAV-delivered artificial miRNAs targeting ataxin-1 to alleviate neuropathological and behavioral phenotypes in the knock-in and transgenic SCA1 mouse models.
In the knock-in SCA1 mouse model AAVs expressing an artificial miRNA (miSCA1) targeting sequences conserved in mouse and human ataxin-1 were injected directly to the deep cerebellar nuclei. This achieved long term silencing of ataxin-1 mRNA and significantly improved rotarod performance, gait deficiencies, and neuropathology of the cerebellum.
In the transgenic SCA1 mouse model the same method of delivery was executed with an artificial microRNA (miR) (miS1) designed to optimize potency, efficacy and safety to suppress Atxn1 expression. Additionally the therapeutic potential of continuous overexpression of ataxin-1-like was examined. Delivery of either ataxin-1-like or miS1 viral vectors to SCA1 mouse cerebellum resulted in widespread cerebellar Purkinje cell transduction. There was significant improvement to rotarod performance, gait deficiencies, coordination and balance, as well as the neuropathology of cerebellar Purkinje cells. In summary, these data indicate the utility of these approaches as possible therapies for SCA1 patients.
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Zhou, Tong. "ROLE OF TYROSYL-DNA PHOSPHODIESTERASE (TDP 1) ON REPAIR OF 3′-PHOSPHOGLYCOLATE (3′- PG) TERMINATED DNA DOUBLE-STRAND BREAKS (DSBS) AND IN RESPONSE TO OXIDATIVE STRESS." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2933.
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DNA DSBs are most toxic to cells because they can lead to genomic rearrangements and even cell death. Most DSBs induced by ionizing radiation or radiomimetic drugs such as calicheamicin and bleomycin, bear 3′-phosphate or 3′- PG moieties that must be removed to allow subsequent gap filling and ligation. DSBs can be repaired by two main pathways: the homologous recombination (HR) pathway and the non-homologous end-joining (NHEJ) pathway, NHEJ is the primary repair pathway in mammalian cells. While HR repairs single strand breaks (SSBs) or DSBs accurately by using an undamaged copy of the sequence mostly at late S phase and G2 phase, the NHEJ pathway repairs DSBs without the requirement for sequence homology in a processing that may be error-free or error- prone and is most active at G1 phase. TDP1 is a DNA repair enzyme in both pathways, It associates with DNA SSB repair proteins XRCC1 and DNA ligase III and plays a role in processing of topoisomerase I- mediated SSBs. Our early results suggested that TDP1 also can remove protruding 3’- PG and other 3’ blocks from DSBs ends in vitro. A homozygous H493R mutation in the active site of TDP1 causes spinocerebellar ataxia with axonal neuropathy (SCAN1), a rare autosomal recessive genetic disease with neurological symptoms including peripheral neuropathy. DNA damage and misrepair can be determined by measuring the incidence of chromosomal aberrations such as rings, breaks, dicentrics, acentric fragments, and translocations in metaphase cells, and micronuclei in interphase cells. To assess the possible role of TDP1 in DSB repair in intact cells, the radiosensitivity of SCAN1 cells was determined by using a dose-fractionation method of irradiation. The data indicated that, when exposed to fractionated radiation doses, the SCAN1 cells were more sensitive than normal cells. Moreover, following treatment of cells with calicheamicin, SCAN1 cells showed a significantly higher incidence of dicentric chromosomes, acentric fragments, and micronuclei compared to normal cells, indicating that calicheamicin-induced DSBs were repaired less accurately and less efficiently, or more slowly in SCAN1 cells than in normal cells. All these results are consistent with a role for TDP1 in repair of 3’-PG DSBs in vivo. Oxidative stress is thought to induce replicative senescence and DNA damage in mouse embryo fibroblasts (MEFs). To determine the possible roles of oxidative stress on Tdp1-deficient MEFs, Tdp1-knockout MEFs and normal MEFs were cultured in 20% oxygen (atmospheric) and 3% (physiological) oxygen. The data from growth assays indicated that normal MEFs showed replicative senescence in 20% oxygen but not in 3% oxygen. Tdp1-knockout MEFs showed very poor growth compared to Tdp1 normal MEFs in both oxygen conditions, clearly suggesting an influence of repair of Tdp1 on oxidative stress induced DNA-DSBs in MEFs. Taken together, our results indicated that TDP1 is capable of removing protruding 3’-PG from DSB ends in intact cells. Moreover, DSBs induced by oxidative stress were repaired more slowly or inefficiently in MEFs when Tdp1 is absent, resulting in cell cycle arrest and poor cell growth.
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Patterson, Erika K. "The social class attitudes scale (SCAS) : instrument development and estimates for reliability and validity /." free to MU campus, to others for purchase, 2003. http://wwwlib.umi.com/cr/mo/fullcit?p3099621.
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Esoof, Noor. "Investigation of the physiological function of TTBK2 (tau tubulin kinase 2), a protein kinase mutated in spinocerebellar ataxia type 11 (SCA11)." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/3e54a702-4da8-4b0e-aab5-c1e693191684.
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TTBK2 was first identified based on its physical association with microtubules and its ability to phosphorylate microtubule-associated proteins (tau, tubulin, MAP2) in vitro (Takahashi et al., 1995, Tomizawa et al., 2001). Since this discovery by Japanese scientists in 1995, considerable work has been invested in examining TTBK2’s relationship with aberrant tau phosphorylation and neurodegeneration in Alzheimer’s disease. However, these studies have never been substantiated in vivo. The identification of TTBK2 truncating mutations as the cause of spinocerebellar ataxia type 11 (SCA11), in 2007, emphasised that TTBK2 has a prominent physiological role in the nervous system. When I started my PhD, there was little known about TTBK2 and many fundamental questions about TTBK2 remained unanswered. In Chapter 3, I describe an initial analysis of TTBK2 substrate specificity by using an unbiased positional scanning peptide library and show that it has a conspicuous preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. This information was then exploited to develop an optimised peptide substrate, named TTBKtide, to assess TTBK2 catalytic activity. TTBKtide was used to demonstrate that SCA11 truncating mutations lead to marked inhibition of TTBK2 kinase activity. The identification of TTBK2’s interacting proteins was of paramount importance to advance our understanding of both biological and disease processes. Identifying and characterising the key targets (substrates) of TTBK2 in the nervous system would provide vital new insights into the physiological role of TTBK2, which in turn, may uncover the molecular pathogenic mechanism underpinning the development of spinocerebellar ataxia type 11 (SCA11). To this end, I identified a number of TTBK2 interactors by co-immunoprecipitation of endogenous TTBK2 from mouse brain homogenates (Chapter 4). This screen provided tantalising evidence that TTBK2 operates in a distinct step of the synaptic vesicle cycle. An analysis of potential protein substrates identified synaptic vesicle glycoprotein 2A (SV2A) as a substrate of TTBK2. Phosphopeptide mapping revealed that SV2A is phosphorylated at two clusters of three highly-conserved residues by TTBK2. These two phosphorylation clusters were then shown to mediate the phospho-dependent interactions of SV2A with AP2 clathrin adaptors and synaptotagmin 1. SV2A and synaptotagmin 1 are both synaptic vesicle membrane proteins. Their interaction is both physical and functional. In chapter 5, I describe the characterisation of the SV2A/synaptotagmin 1 interaction using biophysical and functional methods. I have used two different biophysical methods: Isothermal titration calorimetry (ITC) and fluorescence polarisation, for quantitative analyses of the SV2A/synaptotagmin 1 phosphospecific interaction. Also, in collaboration with Prof. Michael Cousin’s laboratory (University of Edinburgh), the role of SV2A phosphorylation and the effect of disrupting the SV2A/synaptotagmin 1 interaction were examined via mutagenesis and optical imaging of pHluorin-tagged proteins in cultured neurons from wild-type mice.
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Hawkins, Amy. "Nonhomologous end-joining: TDP1-mediated processing, ATM-mediated signaling." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/34.
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This thesis investigates two separate features of nonhomologous end-joining (NHEJ) DNA repair: end processing, and DNA repair kinase signaling. DNA end processing was investigated in a mouse model of hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), a congenital neurodegenerative disease. SCAN1 is caused by a homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1). To address how the H493R mutation elicits the specific pathologies of SCAN1 and to further elucidate the role of TDP1 in processing DNA end modifications, we generated a Tdp1 knockout mouse and characterized their behavior and specific repair deficiencies in extracts of embryonic fibroblasts from these animals. While Tdp1(-/-) mice appear phenotypically normal, extracts from Tdp1(-/-) fibroblasts exhibited deficiencies in processing 3'-phosphotyrosyl single-strand breaks and 3'-phosphoglycolate (PG) double-strand breaks (DSBs). Supplementing Tdp1(-/-) extracts with H493R TDP1 partially restored processing of 3'-phosphotyrosyl single-strand breaks, but with evidence of persistent covalent adducts between TDP1 and DNA, consistent with a proposed intermediate-stabilization effect of the SCAN1 mutation. However, H493R TDP1 supplementation had no effect on PG termini on 3' overhangs of DSBs; these remained completely unprocessed. Altogether, these results suggest that for 3'-PG overhang lesions, the SCAN1 mutation confers loss of function, while for 3'-phosphotyrosyl lesions, the mutation uniquely stabilizes a reaction intermediate. Furthermore, there is evidence that TDP1 also localizes to mitochondria, and mitochondrial DNA damage should not be excluded from significantly contributing to SCAN1 pathology. The effect of ATM signaling on NHEJ was investigated via a novel vector that allows for inducing I-SceI-mediated DNA DSBs that can then be analyzed for NHEJ repair events by fluorescence- and PCR-based methods. Using highly specific DNA kinase inhibitors and the repair cassette, we showed that inhibiting ATM reduced NHEJ by 80% in a U87 glioma model. Analysis of the PCR products from the NHEJ repair vector by PsiI restriction cleavage allowed for assessment of the fidelity of the NHEJ repair: inhibiting ATM reduced high-fidelity NHEJ by 40%. Together, these results suggest that ATM is critical for NHEJ of I-SceI DSBs and for high-fidelity repair, possibly due to ATM's effects on chromatin architecture surrounding the DSB.
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De, Gaspari Piera [Verfasser]. "Lineage tracing of Sca1-expressing cells in the heart and skeletal muscle / Piera De Gaspari." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1075454514/34.
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Landendinger, Melanie [Verfasser]. "Häufigkeit der Spinocerebellären Ataxie Typ 14 (SCA14) in einem Kollektiv von Ataxie-Patienten : Mutationsscreening des Proteinkinase C Gamma-Gens (PRKCG) / Melanie Landendinger." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/106395441X/34.
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Åhlén, Johan. "Pilotstudie av FRIENDS : Ett preventionsprogram för ångestproblematik hos skolbarn." Thesis, Stockholm University, Department of Psychology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-40651.
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Ångestsyndrom tillhör den vanligaste psykiatriska problematiken hos barn. Ångestsyndrom börjar ofta i tidig ålder, medför stort lidande och predicerar psykiatrisk problematik senare i livet. Det är viktigt att undersöka hur ångestsyndrom kan förebyggas eftersom få barn med denna problematik kommer i kontakt med behandling. Syftet med studien var att undersöka om FRIENDS, ett preventionsprogram från Australien, fungerar i en svensk kontext. Femtio barn i nioårsåldern undervisades i FRIENDS under tio lektioner. Barnens ångestsymptom, depressionssymptom och generella psykiska hälsa mättes vid tre tillfällen med formulären SCAS, CDI och SDQ. Mätningarna skedde tio veckor innan interventionen, veckan innan och veckan efter interventionen. Resultaten visade att FRIENDS minskade barnens depressionssymptom samt minskade ångest hos barn med förhöjd risk för ångestproblematik. Efter FRIENDS skattade lärarna lägre tendens till psykisk ohälsa hos barnen. Enligt utvärderingen var barn och föräldrar nöjda med programmet. Sammantaget visar studien att FRIENDS är en lovande intervention i en svensk kontext.
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Hetrick, Shannon. "Examination of Driver Lane Change Behavior and the Potential Effectiveness of Warning Onset Rules for Lane Change or "Side" Crash Avoidance Systems." Thesis, Virginia Tech, 1997. http://hdl.handle.net/10919/36654.
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Lane change or "Side" Crash Avoidance Systems (SCAS) technologies are becoming available to help alleviate the lane change crash problem. They detect lane change crash hazards and warn the driver of the presence of such hazards. This thesis examines driver lane change behavior and evaluates the potential effectiveness of five warning onset rules for lane change or "side" crash avoidance system (SCAS) technologies.
The ideal SCAS should warn the driver only when two conditions are met: (1) positive indication of lane change intent and (2) positive detection of a proximal vehicle in the adjacent lane of concern. Together, these two conditions create a crash hazard. The development of SCAS technologies depends largely on an understanding of driver behavior and performance during lane change maneuvers. By quantifying lane change behavior, real world crash hazard scenarios can be simulated. This provides an opportunity to evaluate potential warning onset rules or algorithms of driver intent to change lanes.
Five warning onset rules for SCAS were evaluated: turn-signal onset (TSO), minimum separation (MS), line crossing (LC), time-to-line crossing (TLC), and tolerance limit (TL). The effectiveness of each rule was measured by the maximum response time available (tavailable) to avoid a crash for a particular lane change crash scenario, and by the crash outcome, crashed or crash avoided, of a particular lane change crash scenario.Master of Science
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Ngwamidiba, Maxime. "Etude moléculaire des gènes SCA1 et SCA2 codant des protéines autotransporteurs chez les membres du genre " rickettsia"." Aix-Marseille 2, 2006. http://www.theses.fr/2006AIX20660.
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Des analyses d'ADN sur les restes des soldats de la Grande Armée de Napoléon (1812) ont révélé la présence entre autre de Rickettsia prowazekii. Pourtant la rickettsiologie ne commençera qu'avec les travaux de Ricketts et von Prowazek en 1910, et ne cessera de s'alimenter d'espèces et de pathologies nouvelles. En tant que premières bactéries intracellulaires strictes décrites, la taxonomie des rickettsies rassemblait initialement sur la base de ce critère, un grand nombre de genres bactériens ultérieurement reclassés avec l'avènement du séquençage et la découverte d'horloges moléculaires telle que la sous-unité 16S de ARN ribosomique ou le cytochrome C. Pour l'identification des espèces de Rickettsia, de nombreux critères phénotypiques dont la morphologie, les tests de fixation du complément, de neutralisation de toxines, de sérotypage et les profils protéiques ont longtemps été utilisés. Mais c'est la comparaison des séquences de gènes, dont ompA, ompB et sca4, qui ont permis d'identifier très précisément les espèces du genre Rickettsia et de proposer une classification phylogénique fiable. Cependant, la position phylogénique d'espèces telles que Rickettsia helvetica, Rickettsia canadensis et Rickettsia bellii n'a pu être déterminée avec certitude. Aussi, l'analyse basée sur la concaténation de plusieurs gènes, associée aux caractères phénotypiques peut constituer une meilleure alternativeThe history of rickettsioses is probably as ancient as human civilisation. The first documented cases of rickettsioses dates back to 1812. In early part of the last century (1910) Ricketts and von Prowazek laid the foundation of modern rickettsiology. Their pioneering works eventually led to the recognition of new species and Rickettsiales infections. As soon as Rickettsia are the first strictly intracellular bacteria described, its taxonomy gathered on the basis of this criterion, and a great number of kinds of bacteria which will be identified only with the advent of the sequencing and the discovery of molecular clocks such as ribosomal 16S RNA and cytochrome C. Many phenotypic criterion such as morphology, tests of complement, neutralization of toxins, mousse serotyping and SDS-page proved reliable. However, gene comparison (ompA, ompB and sca4) will make it possible to very precisely determine the species containing of the genus Rickettsia and to suggest a classification supported by high bootstrap values as well as antibiotics tests. Nevertheless, the phylogenetic position of species such Rickettsia helvetica, Rickettsia canadensis and Rickettsia bellii could not be given with precision, and the polyphasic analysis of the classification of the Rickettsia species based on genes concatenation associated with phenotypic characters available might be alternatives for Rickettsia phylogeny
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Ley, Lea-Theresa [Verfasser]. "Häufigkeit der Spinocerebellären Ataxie Typ 13 (SCA13) bei Ataxie-Patienten : Screening auf Mutationen im KCNC3-Gen unter besonderer Berücksichtigung des Exons 1 / Lea-Theresa Ley." Gießen : Universitätsbibliothek, 2019. http://d-nb.info/1175873640/34.
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Emmel, Vanessa Erichsen. "Análise de repetições CAG nos genes SCA1, SCA2, SCA3 e SCA6 em pacientes com suspeita clínica de ataxia espinocerebelar." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2007. http://hdl.handle.net/10183/10967.
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As ataxias espinocerebelares (SCAs) são doenças neurodegenerativas com herança autossômica dominante que apresentam grande heterogeneidade clínica e genética. O diagnóstico é realizado pela detecção da mutação no gene causador, que, na sua maioria, é uma expansão de repetições trinucleotídicas CAG. O objetivo deste estudo foi analisar os polimorfismos de repetições trinucleotídicas nos genes associados as SCAs tipo 1, tipo 2, tipo 3 e tipo 6 através de PCR-multiplex e eletroforese capilar, visando a melhoria do diagnóstico molecular e a determinação da distribuição das regiões polimórficas nos alelos normais. As análises foram realizadas em 124 pacientes não-aparentados que apresentavam sintomas de ataxia. Nessa amostra, foram identificados 10 pacientes com SCA2, 39 pacientes com SCA3 e 2 pacientes com SCA6. Não encontramos amostras com uma expansão CAG no gene SCA1. Os polimorfismos de cada loci foram estudados nos cromossomos normais desses pacientes (n=209-248). A freqüência dos alelos normais grandes no locus SCA1 (>32 repetições CAG) foi estabelecida em 0,05 e no locus SCA2 (>22 repetições CAG) foi 0,11, enquanto que no locus SCA3 (alelos >28 repetições) a freqüência foi 0,11. A freqüência de alelos normais grandes para o locus SCA6 (>13 repetições) foi 0,04. Concluindo, este estudo proporcionou a primeira análise detalhada da distribuição de repetições CAG nos loci SCA1, SCA2, SCA3 e SCA6 por amplificação multiplex e eletroforese capilar em pacientes brasileiros. A freqüência dos alelos normais grandes nos genes SCA3 e SCA6 nessa amostra reflete a prevalência destas duas doenças na nossa população, concordando com a hipótese que alelos patogênicos podem ser originados pela expansão de alelos normais grandes.Spinocerebellar ataxias (SCAs) are neurodegenerative disorders inherited as an autosomal dominant trait that present large genetic and clinical heterogeneity. An accurate diagnosis relies on mutation detection in a specific causative gene, which is typically an abnormal number of CAG trinucleotide repeats. The aim of this study was to analyze polymorphic regions of trinucleotide repeats in SCA1, SCA2, SCA3, and SCA6 associated genes through multiplex PCR and capillary electrophoresis, aiming the improvement of molecular diagnosis and distribution of CAG repeats number in normal alleles. Analyses were carried out in 124 unrelated Brazilian patients who presented symptoms of progressive ataxia. To date, we identified 10 patients with SCA2, 39 patients with SCA3, and 2 patients with SCA6. No alleles were identified with a CAG expansion tract in the SCA1 gene. Normal CAG repeats length range was established using data from normal chromosomes (n=209-248). Frequency of large normal alleles in SCA1 locus (>32 CAG repeats) was determined to be 0.05. Frequency of large normal alleles at the SCA2 locus (>22 CAG repeats) was shown to be 0.11 while at the SCA3 locus (>28 CAG repeats) frequency of large normal alleles was 0.11. At the SCA6 locus, frequency of large normal alleles (>13 CAG repeats) was found to be 0.04. Moreover, this study provides the first detailed analysis, to our knowledge, of the distribution of CAG repeats at the SCA1, SCA2, SCA3, and SCA6 loci by multiplex-PCR and automated capillary electrophoresis in Brazilian patients. Frequency of large normal alleles in SCA3 and SCA6 genes established in this sample reflects the prevalence of these two diseases in our population, supporting the hypothesis that disease alleles emerge from expansion of large normal alleles.
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Baine, Fiona Kebirungi. "Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa." Master's thesis, University of Cape Town, 2010. http://hdl.handle.net/11427/13436.
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Includes bibliographical references (leaves 118-132).Spinocerebellar ataxia 1 (SCA1) is part of a broader group of dominant neurodegenerative disorders caused by an unstable CAG trinucleotide repeat. There is no known cure for this disease and symptoms worsen progressively culminating in death. The disease-causing mutation in SCA1 occurs in the ATXN1 gene. The function of the gene product (the ataxin-1 protein) is unknown, however; the protein has been linked to RNA processing in the cell. The first part of this study followed on a 1997 report of two founder haplotypes in the Mixed Ancestry SCA1 families in the Western Cape of South Africa, using microsatellites. The aim was to narrow the region investigated in the previous study, and confirm the existence of founder haplotypes using a SNP-based haplotype. The SNPbased haplotype was constructed using 4 SNPs in individuals from 5 different families of Mixed Ancestry origin from the Western Cape and the two founder events were confirmed. The SNP-based haplotype also shows the existence of a minimum common interval and indicates regions of possible break-points which may be useful in determining the extent and origins of the two haplotypes. The second aim of the study was to preferentially silence the mutant transcript of the ATXN1 gene by targeting a single nucleotide difference. Two of the SNPs genotyped for the SNP-based haplotype were found to be heterozygous in over half of the patient cohort. Eight shRNA effector molecules were screened against short target sequences incorporating one of these SNPs. Results are promising, with significant discrimination achieved between the wild-type and mutant alleles by targeting this SNP. This study has shown that RNAi may be developed as a beneficial therapeutic technique for a subset of SCA1 patients in South Africa.
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Houston, Nicola Patricia. "Protein complexes in neurodegenerative diseases." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/7738.
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The 14-3-3 family of proteins are important signalling proteins involved in a number of cellular processes. These include cell cycle regulation, apoptosis, signal transduction and cell signalling. There is also considerable evidence in the literature that 14-3-3 proteins play a vital role in the pathology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s and Prion disease. The neurodegenerative disease of focus in this research is Spinocerebellar Ataxia Type 1 (SCA1). SCA1 is a polyglutamine-repeat disease and the interaction of the disease protein ataxin-1 with 14-3-3 proteins leads to the toxic accumulation and subsequent protein aggregation which is characteristic of this disease. This study focused on attempting to elucidate the structure of various domains of the disease protein and also in identifying potential inhibitors of this deleterious interaction. Unfortunately, structural studies were not successful due to a number of caveats encountered in the expression and purification of the ataxin-1 protein domains. By utilising computational methods and small molecule inhibitors, a number of potential lead compounds which possess the ability to at least partly disrupt the interaction of 14- 3-3ζ have been identified. As 14-3-3 proteins play roles in other neurodegenerative diseases, successful identification of potential drug lead treatments can have far reaching benefits in a number of neurodegenerative diseases including SCA1. Lipid rafts are also involved in neurodegenerative disease pathology. Lipid rafts are cholesterol and sphingolipid rich domains which organise the plasma membrane into discrete microdomains and act as signalling platforms and processing centres which attach specific proteins and lipids. A number of disease proteins are processed at these membrane regions, including those involved in Alzheimer’s, Parkinson’s and Prion disease. This processing is a step which is critical in the pathology of disease and abnormal processing leads to the formation of toxic protein aggregates. Previous research in the lab identified the association of low levels of the five main brain isoforms of 14-3-3 proteins with rafts. This study expanded on this to positively identify the presence of the two phospho-forms of 14-3-3, α and δ. The mechanism by which 14-3-3 proteins associate with rafts was also investigated, indicating that 14-3-3 associates with rafts via an unidentified raftbound protein(s). In addition, the phosphorylation status and quaternary structure of 14-3-3 in the presence of sphingolipids has been explored.
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DeSousa, Diogo Araújo. "Instruments to assess anxiety symptoms in brazilian population and the case of the Spence Children's Anxiety Scale (SCAS) : cross-cultural adaptation and psychometric properties." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/79939.
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Esta dissertação é composta por quatro estudos acerca de instrumentos para a avaliação de sintomas de ansiedade. O objetivo do Estudo 1 foi realizar uma revisão sistemática dos instrumentos disponíveis para avaliar sintomas de ansiedade e transtornos de ansiedade (TA) em população brasileira. O objetivo do Estudo 2 foi realizar o processo de adaptação transcultural da Spence Children’s Anxiety Scale (SCAS) para o Brasil. O objetivo do Estudo 3 foi examinar a sensibilidade e especificidade da Screen for Child Anxiety Related Emotional Disorders (SCARED) para o diagnóstico de TA em uma amostra comunitária de crianças e adolescentes brasileiros. O objetivo do Estudo 4 foi investigar as propriedades psicométricas da SCAS em amostras comunitária e clínica de crianças e adolescentes brasileiros. Os resultados do Estudo 1 fornecem um panorama das características e evidências de adequação dos instrumentos disponíveis para avaliar sintomas de ansiedade e TA em população brasileira. Os resultados dos Estudos 2, 3 e 4, em conjunto, apresentam a versão brasileira da SCAS como um instrumento adequado para avaliar sintomas de ansiedade infantil em contextos comunitário e clínico no Brasil. Implicações para a avaliação e o tratamento psicológico e psiquiátrico de TA são discutidas.This Master Thesis encompasses four studies about instruments to the assessment of anxiety symptoms. The aim of the Study 1 was to conduct a systematic review of the instruments available to assess anxiety symptoms and anxiety disorders (AD) in Brazilian population. The aim of the Study 2 was to perform the cross-cultural adaptation process of the Spence Children’s Anxiety Scale (SCAS) to Brazil. The aim of the Study 3 was to examine the sensitivity and specificity of the Screen for Child Anxiety Related Emotional Disorders (SCARED) to the diagnosis of AD in a community sample of Brazilian children and adolescents. The aim of the Study 4 was to investigate the psychometric properties of the SCAS in a community and a clinical sample of Brazilian children and adolescents. Results from Study 1 provide an overview of the characteristics and the adequacy evidences of the instruments available to assess anxiety symptoms and AD in Brazilian population. Results from Studies 2, 3, and 4, altogether, present the Brazilian version of the SCAS as an instrument suitable to assess pediatric anxiety symptoms in Brazilian community and clinical settings. Implications for the psychological and psychiatric assessment and treatment of AD are discussed.
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Sundqvist, Linnéa, and Susanna Hillborg. "Hur kan företag med lågengagemangsprodukter gå tillväga för att uppnå emotionell och sann lojalitet gentemot kunderna? : En kvalitativ studie på SCAs produkter Edet papper och Libresse." Thesis, Södertörns högskola, Institutionen för ekonomi och företagande, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:sh:diva-16821.
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In a competitive market as supermarkets, hundreds of the same products fight for attention in the shops. Every day thousands of targeted advertising messages is given to us. As a natural result of all this, power is transferred to consumers. You can no longer differentiate yourself by only price and function, thus companies must play on the emotional aspects and create a relationship with consumers. A key to success is to understand people's emotional needs and then satisfying them. In various journals and papers you can find highlighted success stories of strong brands such as Harley-Davidson, Apple and Virgin Airlines. They have all grown strong passionate relationships with their customers. It describes the type of emotional loyalty that all companies strive to achieve. But what about the marketers who face the same challenge, though they will sell toilet paper rather than a motorcycle? Where consumers think that the product in question is boring but necessary evil? Can these products even achieve an emotional relationship with their customers? Low-engagement products often have many loyal customers. Since you do not put so much thought behind the purchase, you choose the same brand on a regular basis again and again. It is thus a loyal customer, but customers often have not reflected on why they are that. The client therefore has no emotional connection to the product. This type of behavior is classified as "false loyalty" and is often based on the customer buying the product of habit and by means of short memory rules. The opposite of this false loyalty is "true loyalty" and may also be termed as "emotional loyalty" where the customer purchases the product on a regular basis because of the perceived value, how much the customer likes the product and what positive feelings and associations the customer has to the product. People strive to experience positive emotions and want to avoid negative ones. This means that if a consumer is experiencing a positive feeling, it is expected that he would endeavor to repeat it, and thus become a loyal customer. This shows that one can connect emotion and loyalty to each other, which we will do in this paper. We have in our study used a qualitative method and with a positivistic approach. We have conducted interviews with two respondents from the company SCA; Camilla Svensson on Edet and Margareta von Renteln on Libresse. We have, through our investigation concluded that it is possible for low-engagement products to achieve emotional and true loyalty to customers, but it is very difficult when compared with a high-engagement product. One must also consider that even low-engagement products have varying degree of commitment. A feminine hygiene product implies a higher risk when compared to a toilet paper. Therefore promotional activities must be adjusted by type of asset.Inom en konkurrensutsatt marknad som livsmedelshandeln slåss hundratals homogena produkter om uppmärksamheten i butikshyllorna. Varje dag riktas tusentals olika reklambudskap mot oss. Som en naturlig effekt av allt detta har makten överförts till konsumenterna. Man kan inte längre differentiera sig genom endast pris och funktion, därmed måste företagen spela på de emotionella aspekterna och skapa en relation till konsumenterna. En nyckel till framgång är att förstå människors emotionella behov och sedan tillfredsställa dessa. I olika tidskrifter och uppsatser lyfts framgångshistorier om starka varumärken såsom Harley-Davidson, Apple och Virgin Airlines fram, som alla har odlat starka passionerade band till sina kunder. Det beskriver den typ av emotionell lojalitet som alla företag strävar efter att uppnå. Men hur går det för marknadsförare som ställs inför samma utmaning, fast de ska sälja toalettpapper snarare än en motorcykel? Där konsumenterna rent av tycker att produkten i fråga är tråkig men ett nödvändigt ont. Kan dessa produkter även uppnå en emotionell relation till sina kunder? Lågengagemangsprodukter har ofta många lojala kunder. Eftersom man inte lägger så mycket tankeverksamhet bakom köpet, så väljer man samma varumärke regelbundet om och om igen. Man är alltså en lojal kund, men kunden har ofta inte reflekterat över varför denne är det. Kunden har alltså ingen emotionell koppling till produkten. Denna typ av beteende klassificeras som ”falsk lojalitet” och bottnar ofta i att kunden köper produkten av gammal vana och med hjälp av korta minnesregler. Motsatsen till denna falska lojalitet kallas “sann lojalitet” och kan också benämnas som ”emotionell lojalitet” där kunden köper produkten regelbundet på grund av det upplevda värdet, hur mycket kunden gillar produkten samt vilka positiva känslor och associationer som produkten väcker. Människor strävar efter att uppleva positiva känslor och vill undvika negativa sådana. Detta innebär att om en konsument upplever en positiv känsla, kan det förväntas att denne skulle sträva efter att upprepa detta och därmed bli en lojal kund. Därmed så kan man koppla ihop emotion och lojalitet med varandra, vilket vi kommer att göra i den här uppsatsen. Vi har i vår undersökning använt oss av en kvalitativ metod och med ett positivistiskt synsätt. Vi har fört djupintervjuer med två respondenter från företaget SCA; Camilla Svensson på Edet och Margareta von Renteln på Libresse. Vi har genom vår undersökning kommit fram till att det är möjligt för lågengagemangsprodukter att uppnå emotionell och "sann lojalitet" gentemot kunderna, men att det är mycket svårare om man jämför med en högengagemangsprodukt. Man måste även beakta att även lågengagemangsprodukter har varierande engagemangsgrad. Ett menstruationsskydd innebär en högre risk om man jämför med ett toalettpapper. Därför måste marknadsföringsaktiviteterna anpassas efter varutyp.
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Socal, Mariana Peixoto. "Genes principais e genes predisponentes à doença de Parkinson : estudo sobre os genes PARK2, PARK6, PARK7, PARK8, SCA1, SCA2, SCA3, SCA6, SCA7 e o gene da glucocerebrosidase." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2008. http://hdl.handle.net/10183/16850.
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A doença de Parkinson é freqüente no mundo todo, atingindo indivíduos de todas as idades e etnias. Embora comum e muito estudada, seus mecanismos causais ainda não são plenamente conhecidos e ainda não há tratamento curativo. Atualmente, são conhecidos alguns fatores ambientais e genéticos associados ao desenvolvimento da doença de Parkinson. Dentre os fatores genéticos, foram identificados diversos genes que podem, ou determinar a ocorrência da doença de forma mendeliana (genes principais), ou apenas aumentar o risco de seu surgimento (genes de suscetibilidade). Embora os fatores genéticos, em conjunto, sejam responsáveis por uma minoria dos casos, permanece relevante esta investigação, para promover um aconselhamento genético adequado para os portadores de formas mendelianas, para adequar medidas de tratamento e reconhecer características clínicas e de prognóstico, oportunizando, inclusive, ampliar o entendimento dessa condição. O presente estudo analisou pacientes portadores de doença de Parkinson em acompanhamento no Hospital de Clínicas de Porto Alegre, que apresentavam baixa idade de início dos sintomas, história familiar positiva ou presença de manifestações atípicas da doença. Essas características foram utilizadas como critério de seleção dos pacientes por estarem associadas com maior probabilidade de detecção de causas genéticas. Os pacientes foram submetidos à avaliação clínica e à testagem molecular para diversos genes principais e de suscetibilidade. Foram, posteriormente, comparadas as características clínicas dos pacientes positivos com relação aos demais pacientes estudados. Os resultados são apresentados sob a forma de três artigos, que descrevem, respectivamente, os achados moleculares da investigação para os genes causais autossômicos recessivos (genes PARK2, PARK6, PARK7 e PARK8), autossômicos dominantes (genes SCA1, SCA2, SCA3, SCA6 e SCA7) e o gene de suscetibilidade (gene GBA).
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Hourez, Raphaël. "Dysfonction des cellules de Purkinje du cervelet dans l'ataxie spino-cérébelleuse de type 1 (SCA1), le syndrome alcoolique foetal et lors de la modulation d'expression de Nogo-A." Doctoral thesis, Universite Libre de Bruxelles, 2007. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210583.
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Olivier, Andries J. "Effek van projektiewe narratiewe op kinders in kinderhuise se tekeninge van vrees." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/3047.
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Thesis (MEdPsych (Educational Psychology)--Stellenbosch University, 2008.The study investigated the effect of using projective narratives and drawings that depict diminished fear, on the anxiety levels of a group of children living in children’s homes, by means of a mixed methodology. The sample consisted of 30 middle childhood children (mean age = 9.60 years, SD = 1.13) from three children’s homes in the Western Cape. Drawings were used to elicit content of fear or anxiety (anxiety evoking drawing/bangmaaktekening) and proposed coping (anxiety lessening drawing/bangwegvattekening). After completing the anxiety provoking drawing, participants in the experimental group were asked to tell a story to other children with a similar fear to lessen/take that fear away (projective narrative). The Spence Childhood Anxiety Scale (SCAS) was completed after each drawing, and drawings evaluated through the use of anxiety scales, to measure changes in anxiety levels according to the concept of triangulation. The categories ghosts, snakes, and people were found to be the most prevalent content of fear from anxiety provoking drawings, and undifferentiated fears were also common within this population. Control of anxiety from anxiety lessening drawings indicated a definite prevalence of emotion focused (secondary) coping strategies, specifically religious solace. The content of projective narratives echoed this finding, although proposed solutions were more differentiated. Ownership of projections also occurred. The experimental effect was not significant, although mean anxiety levels were considerably lower in the drawings in comparison with that of the SCAS. Drawings are thus seen as an effective, nonthreatening technique to study anxiety phenomena. A comparison of the mean item scores of the SCAS subscales indicated that symptoms of separation anxiety, generalised anxiety disorder, and obsessivecompulsive anxiety disorder were prevalent among this group of children in children’s homes. A clear distinction was found between markers of state- and trait-anxiety through the qualitative analysis of the drawings, with anxiety lessening drawings showing definite diminished state-anxiety, although more established markers of trait-anxiety did not necessarily change. There are also indications that transference of activated negative emotional stimuli occurred on an unconscious level between the two drawings. Introducing the combination of projective narratives in the intervention stage of the study appeared to facilitate learning or the experience of observed positive affect in anxiety lessened drawings. Future research would benefit from including a normative group to establish more clear markers of state- and trait-anxiety in drawings, and by the use of a bigger sample to investigate factor loadings of the SCAS among children in children’s homes. The high prevalence of anxiety symptoms in this population emphasises their status as a vulnerable population, and the need for possible group intervention – specifically the psycho-education of effective coping strategies for anxiety.
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Šuminaite, Daumante. "Elucidating the reversibility of ataxia." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28911.
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Heterozygous and recently identified homozygous mutations in the SPTBN2 gene, encoding b-III spectrin, are implicated in spinocerebellar ataxia type 5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type 1 (SPARCA1), respectively. Our mouse model, lacking b-III spectrin (KO), mimics the progressive human phenotype displaying motor deficiencies as well as reduced Purkinje cell firing frequency followed by dendritic tree degeneration and cell death. The aims of this study were to evaluate progression of Purkinje cell degeneration following loss of b-III spectrin function and determine whether the reintroduction of C-terminus (C-trm) of b-III spectrin to the cerebellum is enough to halt, alleviate or reverse the disease phenotype. Additionally, this study investigated whether the abnormal electrophysiological and morphological phenotypes of Purkinje cells from KO mice are re-capitulated in a primary cerebellar culture and if so, whether they could be rescued by modulating calcium signaling. Morphological and histological analyses revealed that Purkinje cell degeneration is not uniform throughout the cerebellum of KO mice with Purkinje cells from posterior cerebellar regions possessing significantly smaller dendritic trees when compared to anterior cerebellum (p=0.0003, N=4-6, n=11-29). Similarly, significant reduction in Purkinje cell density was observed in posterior, not anterior regions of KO mice when compared to WT animals (p=0.014, N=3) and reduced tonic firing is most significant in Purkinje cells from the posterior cerebellum compared to WT mice (p=0.0328, N=3-6, n=11-29), with posterior KO PCs appearing to have elevated input resistance. Two-week expression of C-trm b-III spectrin in 3-month old KO animals significantly reduced Purkinje cell input resistance when compared to non-transduced cells (p=0.0139, N=4-5, n=15), but no effect was seen 9 months after viral injection. In contrast, a difference in cell surface area was no longer detected between WT and KO animals at 12 months of age following 9-months of viral expression. Nevertheless, using the elevated beam test motor deterioration was still observed 5 months after surgery (p=0.0023, N=4). In contrast, earlier stereotaxic injections at 6-weeks of age had a positive effect on mice motor performance with no deterioration in performance detected 5 months after the surgery. Latency to stay on the rotarod at 3 rpm was also significantly extended 6 months after stereotaxic injections at 6-weeks of age with slower motor deterioration (p=0.0348, N=6). In primary cerebellar cultures, Purkinje cells from KO animals exhibit an abnormal morphology with significantly more dendritic branches (p < 0.0001, N=4-7, n=35-69) and a larger total dendritic length (p=0.0079). Chronic application of 2 μM mibefradil, a T-type calcium channel blocker, was observed to reduce total dendritic length and branching in KO animal cultures bringing these morphological measurements closer to WT Purkinje cell levels. Finally although after 14 days in vitro 40% of Purkinje cells were found to be spontaneously firing, no significant difference in firing frequency (p=0.9434) or input resistance (p=0.8434, N=4, n=6-10) was detectable between WT and KO cultures. In summary, Purkinje cells in posterior cerebellar regions of KO mice were found to be more susceptible to dendritic degeneration and cellular death than cells in the anterior cerebellum. Expression of C-trm b-III spectrin at 3 months of age had an immediate effect on cell input resistance and a modest effect on Purkinje cell morphology but no effect on motor decline. Viral injections at 6-weeks of age, however, significantly slowed motor decline. Although an abnormal KO cell morphology could be successfully recapitulated in primary cell culture, it was not possible to discern any differences in electrophysiological properties. Nevertheless, the abnormal cell morphology was successfully modified in vitro by manipulating calcium signaling via T-type calcium channels.
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Xie, Yao. "Leptin induces Sca-1+ progenitor cell migration enhancing neointimal lesions in vessel-injury mouse models." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/leptin-induces-sca1-progenitor-cell-migration-enhancing-neointimal-lesions-in-vesselinjury-mouse-models(a2ab79ee-8438-48dc-adac-4121d26bc2ef).html.
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Leptin is a hormone predominantly secreted by white adipose tissue which was initially believed to be solely a metabolic factor. Recent publications showed that leptin also played a role in inflammation and vascular disease, to which Sca-1+ vascular progenitor cells within the vessel wall may contribute. However, the effect of leptin on vascular progenitor cells remains unknown. In the present study, we sought to elucidate the effect of leptin on Sca-1+ progenitor cells and neointimal formation, and to understand the underlying mechanisms. Sca-1+ progenitor cells from the vessel wall of C57BL/6J (Lepr+/+) and db/db (Lepr-/-) mice were cultured and purified with microbeads. The migration of Sca-1+ progenitor cells in vitro derived from Lepr+/+ mice was markedly induced by leptin. Western blotting and kinase assays revealed that leptin induced phosphorylation of STAT3, ERK1/2, FAK, and Rac1/Cdc42. Guide-wire injury of the femoral artery was performed in wild-type mice with neointimal development in a time-dependent manner. An increased expression of leptin in both injured vessels and serum was observed at 24 hours post-surgery. Red fluorescent protein (RFP) labelled-Sca-1+ progenitor cells in Matrigel were applied to the adventitia of the injured femoral artery, RFP+ cells were observed in the intima at 24 hours post-surgery, which significantly enhanced neointimal lesions at 2 weeks. This increase in neointimal lesions was reduced by pre-treatment of Sca-1+ cells with CYT-354 (leptin antagonist). Moreover, guide-wire injury could only induce minor neointima in Lepr-/- mice at 2 and 4 weeks post-surgery. However, transplantation of Lepr+/+ Sca-1+ progenitor cells into the adventitial side of the injured femoral arteries of Lepr-/- mice significantly enhanced the neointimal formation. In summary, upregulation of leptin levels in both the vessel wall and the circulation following vessel injury resulted in the migration of Sca-1+ progenitor cells, which enhanced neointimal formation via leptin receptor-dependent STAT3- Rac1/Cdc42-ERK-FAK pathways.
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Chen, Hsiang-Ming, and 陳襄銘. "Spinocerebellar ataxias: Genetic testing of SCA2、SCA14 and interaction analysis between expanded SCA17 TBP and HMGB1." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/34332651521942248348.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
95
Spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders characterized by cerebellar dysfunction alone or in combination with other neurological abnormalities. More than 28 SCA types have been described. Among them, SCA2 and SCA17 were caused by the expansions of coded CAG trinucleotide repeats and SCA14 cause by mutations in the protein kinase Cγ. We examined the CAG repeat range of SCA2 Ataxin-2 gene in 179 normal controls and in patients with various neurodegenerative diseases, including 15 ataxia, 137 Parkinson's disease, 124 dementia, 84 essential tremor, and 41 chorea and dystonia. No SCA2 expanded allele was found. In the screening of SCA14 PRKCG gene mutation, we sequenced the exons 4 and 5-containing DNA fragment from 30 patients with parkinsonism and again no mutation was found. To study the protein-protein interaction between HMGB1 and TBP, GST fused HMGB1, nTBP-Q20/Q45/Q61 (N-terminal TBP) and fTBP-Q20/Q45/Q61 (full-length TBP) were overexpressed in E. coli BL21 cells and purified by affinity chromatography. Quartz Crystal Microbalance (QCM) was used to study the interactions between HMGB1 and TBP protein carrying 20, 45 or 61 polyQ track. While the interaction between HMGB1 and full-length or N-terminal TBP was similar, the length of polyQ track affects the binding of HMGB1 to TBP, with strongest binding of nTBP-Q45 (ΔHz = 13.0) and weakest binding of nTBP-Q61 (ΔHz = 4.3).
30
Tao, Yu-Chen, and 陶育晨. "Evaluation of effect of HDAC inhibitors on SCA17 with SCA17 mouse slice culture and transgenic mice." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/06941418884344658241.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
101
Spinocerebellar ataxia type 17 (SCA17) is a polyQ neurodegenerative disease caused by abnormal CAG repeat expansion of TATA-box binding protein (TBP) gene. The CAG trinucleotide expansion results in the mutant polyQ TBP protein misfolded and accumulated in the cells, which further caused the neuronal lose, especially the cerebellar Purkinje cells. Ataxia, motor dysfunction, and dementia are clinical symptoms of SCA17. As the role of TBP being critical in transcription initiation, improving the transcriptional activity by histone deacetylase inhibitors (HDACi) becomes an attractive approach for SCA17 treatment. We have screened several HDACi compounds and found that LBH589 could significantly reduce the TBP aggregation on SCA17 cerebellar slice culture. In in vivo study, we found LBH589 couldn’t ameliorate the motor function and the pathology of SCA17 mice. Additionally, the appetite of mice was reduced and the central nervous system was impacted by LBH589 treatment. We could not suggest that LBH589 is potential in SCA17 treatment from our in vivo results.
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Wang, Chien-Ming, and 王建民. "Identification of Neurotherapeutics for SCA17 Using Transgenic Mouse Model." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/2m97aw.
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Chung, Yu-Han, and 鍾妤涵. "Investigation of neuroinflammatory pathogenesis and therapeutics using SCA17 transgenic mice." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/baw8f5.
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Hübner, Joachim [Verfasser]. "Augenbewegungsstörungen bei spinozerebellärer Ataxie Typ 17 (SCA17) / vorgelegt von Joachim Hübner." 2009. http://d-nb.info/99721466X/34.
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Lin, Chun-Wei, and 林峻緯. "Evaluation of the Effect of Valproic Acid on SCA17 Transgenic Mice." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/17396227772712660765.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
98
Spinocerebellar ataxia type 17 (SCA17), an autosomal dominant and progressive neurodegenerative disease, is caused by a CAG repeat expansion in the gene encoding transcription factor TBP. Several clinical symptoms, such as ataxia, dystonia, parkinsonism, dementia and seizures could be identified in SCA17 patients. Furthermore, loss of cerebellar Purkinje cells could be found in both SCA17 patients and our SCA17 transgenic mice. Purkinje cells are a class of GABAergic neuron located in the cerebellar cortex, which are fundamental for integration of sensory and motor information in motor coordination. Once the Purkinje cells died, the function of cerebellum would be affected. Valproic acid (VPA), a short chain fatty acids histone deacetylase inhibitor (HDACi) compound which can raise the concentration of GABA in the brain by inhibit GABA transaminase activity, has been reported as an effective molecule in neurodegenerative disease models such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) mouse models. In vitro studies also showed that VPA can reduce polyglutamine (polyQ) toxicity and protect neurons. In this study, SCA17 transgenic mouse model, whose ataxia phenotype and Purkinje cell lose has been confirmed, were treated with 0.26% w/v VPA in daily drinking water from the age of 4 weeks. The rotarod task analyses have shown a significant improvement in motor coordination in transgenic mice after treated with VPA, and the neuronal protection effect on Purkinje cell survival and cell morphology were also identified by immunohistochemical and immunofluorence staining. These results reveal that VPA could be a potential compound for SCA17 therapy. The molecular mechanisms of VPA effect on SCA17 mouse model will be further investigated and should uncover more information in SCA17 pathogenesis.
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Chang, Ya-Chin, and 張雅津. "Therapeutic evaluation of granulocyte colony-stimulating factor on SCA17 transgenic mice." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/90829577564732332057.
Full textAbstract:
博士國立臺灣師範大學
生命科學研究所
99
SCA17 is an autosomal dominant cerebellar ataxia (ADCA) caused by the polyglutamine (polyQ) expansion of transcription factor TATA binding protein (TBP). The length of polyQ tract encoded by the CAA/CAG repeats of TBP gene is related to the disease severity. The range of CAG repeats is 25-42 in normal population and 47-55 in SCA17 patients. We speculated that TBP trinucleotide expansion might disrupt comformation of protein folding and lead to cell death. To investigate the TBP trinucleotide expansion effect on neurodegeneration, our previous studies have generated transgenic (TG) mice expressing the human TBP (hTBP) gene with expanded 109 CAA/CAG tracts under the control of Purkinje cell-specific promoter, Pcp2/L7 promoter. These TG mice showed ataxia and reduced rotarod latency compared to their wild-type (WT) littermates. Immunohistochemical analysis has shown that the Purkinje cells in transgenic mouse cerebellum were lost severely. Furthermore, we confirmed that hTBP109Q TG mice had calbindin, inositol 1,4,5-triphosphate receptor 1 (Itpr1) and Cacna1g downregulated by both cDNA microarray and Western blot analysis. This result suggests that transgene expression in the mouse brain might result in the impairment of calcium homeostasis, which may in turn causes the neuron degeneration and ataxia. Reactive gliosis and neuroinflammation were also occurred in the TG mouse cerebellum showing the upregulation of GFAP and Iba1. The hTBP TG disease model recapitulates the phenotypes of SCA17 patients. This model could help us to gain more insight about the molecular pathogenesis and can be used as a platform for drug testing. We thus applied G-CSF on these mice to identify whether it could ameliorate the phenotypes of TG mice. Our results showed that G-CSF treatment at post-symptomatic stage could activate p-ERK survival pathway and showed neuroprotective effect on SCA17 transgenic mice. Compared to the late stage treatment, the G-CSF treatment at the pre-symptomatic stage showed increasing of Hsp70 expression level, which could retard the phenotype on the pathology and behavior of transgenic mice and result in a neuroprotective effect. G-CSF treatment of SCA17 mice also increased LC3-II/Actin ratio which suggested an increasing autophagy activity and enhanced the clearance of SCA17 protein. We conclude that at both the pre-symptomatic or post-symptomatic stages, G-CSF has neuroprotective effect on SCA17 mice. G-CSF may be a potential therapeutic drug for the treatment of SCA17 disease.
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Wang, Pin-Rong, and 王品蓉. "The Effects of HSPs Overexpression and Oxidative Stress in SCA17 Cell Model." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/2c6pht.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
97
Autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders involving progressive degeneration of the cerebellum, brainstem, and spinal tract. More than 28 subtypes have been reported. SCA17 is caused by an expanded polyglutamine (polyQ) in a general transcription initiation factor, the TATA-box binding protein (TBP). The mutated TBP with polyQ expansion causes a conformational change to promote misfolding and aggregation. Futhermore, a polyQ mutation can induce reactive oxygen species (ROS) that directly contribute to cell death. During oxidative stress, synthesis of several heat shock proteins (such as HSPA5, HSPA8 and HSPB1 chaperones) increase to protect cells against oxidative stress. Chaperones may modulate polyQ protein toxicity by stabilizing the misfolded conformation to reduce aggregate formation. Investigation of chaperones and oxidative stress associated with SCA17 may not only contribute to the understanding of molecular mechanism of the disease but also provide therapeutic strategy to slow down the disease progression. By establishing stably induced cell model, the study results revealed that TBP with expanded polyQ formed nuclear aggregates with significant increase in sub G1 phase of cell cycle. Cells expressed polyQ-expanded TBP display increased ROS production and increased sensitivity to staurosporine treatment and serum deprivation. Using transient cell model, HSPA5, HSPA8 and HSPB1 overexpression can reduce aggregate formation.
37
Huang, Shih-Han, and 黃詩涵. "Screening of Novel Compounds and Oxidative Stress Studies using SCA17 Cell Model." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/05417256612718081552.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
99
Spinocerebellar ataxias 17 (SCA17) has been attributed to CAG repeat expansions in human TATA-box binding protein (TBP) gene. The CAG repeats code for polyglutamine (polyQ) tract. The polyQ tract contains 25~42 polyQ in normal population while expanded 43~66 polyQ is linked to SCA17. The polyQ expansions cause a conformational change in the polypeptide to promote misfolding and aggregation of the disease protein, which ultimately forms insoluble protein inclusions. Accompanying increasing insights into the pathophysiology of repeat expansion, much progress has been made to develop therapeutics. In this study, the 293 cells expressing EGFP-tagged polyQ-expanded N-terminal TBP were established and treated with the synthesized indole and quinoxaline compounds (provided by Drs Ching-Fa Yao and Kwunmin Chen). The effects of compounds on inhibiting polyQ aggregation were examined by counting aggregates numbers and quantifying insoluble nTBP-EGFP levels on EGFP-positive cells. The results illustrate that compounds 338 reduce aggregation to a level slightly better than that of SAHA (64.3% vs. 66.1%；70.7% vs. 77.4%). Among them, the IC50 of compound 338 (396 μM) is much higher than that of SAHA (31.4 μM), indicating that 338 may be a lead compound for SCA17 therapeutic development. As the polyQ expansions can induce reactive oxygen species (ROS) to lead to mitochondria impairment, age- and gender-matched lymphoblastoid cells were used to examine the roles of oxidative stress in SCA17 pathogenesis. The results demonstrate oxidative vulnerability of cells carrying expanded TBP. Key words: SCA 17, polyglutamine (polyQ), oxidative stress
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Sun, Ting-Chung, and 孫定中. "Identification of Potential HDAC Inhibitor Compounds for PolyQ Diseases with SCA17 Mouse System." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/95126746126337876891.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
102
Spinocerebellar ataxia (SCA) is a group of heterogeneous autosomal dominant neurodegenerative diseases. Clinical symptoms include ataxia, dementia, dystonia, seizures, and significant cerebellum atrophy in pathology. Spinocerebellar ataxia type 17 (SCA17) is one type of SCAs. It is caused by CAA/CAG repeat segment of the TATA-binding protein (TBP) gene. TBP is a crucial transcription factors for all the three RNA polymerase in transcription initiation. The polyglutamine (polyQ)-expanded mutant TBP accumulates as aggregates in the cells and leads to cell degeneration, especially the cerebellar Purkinje neurons. Histone deacetylases (HDAC) make the histones more tightly bind to DNA by removing the acetyl groups from histones, which in turn suppresses the gene transcription and causes many diseases. HDAC inhibitors could alleviate transcription suppression and show neuroprotecive effect in several neurodegenerative diseases. We used the mouse cerebellar primary culture from the SCA17 transgenic mice established in our lab to screen HDAC inhibitors. The potential compounds were further applied for in vivo test. We found two HDAC inhibitors, NC105 and NC109, can increase Purkinje cell total neurite lengthon primary culture and decrease TBP aggregation on slice culture. These two HDAC inhibitors were applied to small-scale SCA17 mice to verify their efficacy in vivo. During the in vivo treatment, mouse body weight was not altered by HDACi treatment. In addition, mouse motor coordination was improved from the rotarod task evaluation. Our preliminary results show these two inhibitors alleviate Purkinje cell degeneration and increase histone acetylation. NC105 and NC109 treatment can also decrease TBP aggregation. These compounds might alleviate the transcriptional dysfunction of SCA17 through inhibition of HDAC. These two HDAC inhibitors also could significant improved mouse motor coordination from the behavior evaluation for large scale animal test. In sum, NC105 and NC109 show significant effect in vitro and improve motor coordination and reduce neuron degeneration of SCA17 transgenic mice. The result suggests that these two HDACi could be potential HDAC inhibitors for SCA17 treatment.
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Hsu, Chen-Ming, and 許振銘. "Evaluation of the therapeutic potential of SAHA and L-BMX on SCA17 mice." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/80187900300531324947.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
100
Spinocerebellar ataxias (SCA) 17, is a late onset neurodegenerative disease caused by abnormal CAG/CAA overexpansion in the coding region of the TATA-box binding protein (TBP) gene on chromosome 6q27. The N-terminal polyglutamine (polyQ) overexpansion of TBP leads to intercellular toxicity in central nervous system. The symptoms of SCA17 patients are similar to that of Huntington’s disease (HD), including ataxia, seizure, cognitive dysfunctions, psychiatric symptoms, dystonia, and chorea. The epigenetic regulation of chromatin modification, such as histone acetylation, is widely used in cancer therapy. In recently study, histone deacetylase inhibitors (HDACi) was shown to play a role in neuron protection both in vivo and in vitro. In this study, we applied a widely-used HDACi, suberoylanilide hydroxamic acid (SAHA), and a novel HDACi, L-BMX, on the hTBP-109Q transgenic (TG) mice to assess their therapeutic potential on SCA17. Our preliminary result showed these two HDACi treatment have mild therapeutic effect on cerebella pathology of transgenic mice through immunostaining analyses. Behavior test with rotarod showed that animals could not benefit from the long-term treatment of these two HDACi compounds. However, under the low strength behavior tests, footprint and beam test, mice showed better performance with SAHA or L-BMX treatment than the non-treated TG control mice. These results revealed that SAHA and L-BMX might have mild beneficial effect on SCA17 mice. In addition, to further elucidate the neuropathology of the hTBP-109Q transgenic mice, we used immunofluorescent staining and electron microscope (EM) analyses to study the pathological profile of mouse cerebellum and Purkinje cells, respectively. These data should provide us more information for the pathogenesis and therapeutic design for SCA17.
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Chen, Wei-i., and 陳偉毅. "Evalution of the effect of curcumin on SCA17 slice culture and transgenic mice." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/85444139535973467894.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
98
Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease attributed to polyglutamine (polyQ) expansions within the human TATA-box binding protein (TBP). The misfolding of polyQ tract forms nuclear aggregates in SCA17 patients impact the neuron function, leading to cerebellar atrophy, Purkinje cell loss and severe clinical phenotype includes ataxia, dystonia, parkinsonism, dementia and seizures. Curcumin (diferuloylmethane) is well known for its ability to scavenge free radicals and inhibit inflammation. Several studies have suggested the potential of curcumin in treatment of neurodegenerative diseases. To investigate the therapeutic potential of curcumin for polyQ-mediated SCA17, we treated SCA17 transgenic mice with curcumin diet. Our data showed that curcumin could ameliorate the neurologic behavioral deficiency, balance function and motor coordination of SCA17 transgenic mice. Results of pathology examination indicated that curcumin diet could rescue cerebellar atrophy, reverse Purkinje cell shrinkage and trend to reduce apoptosis in mice. Moreover, the inflammatory level and gliosis were also reduced in curcumin treated SCA17 transgenic mice. To have a quick platform for evaluating potential compounds for SCA17, we also established an organotypic cerebellar slice culture system using postnatal day 7 mouse tissues. During the ex vivo culture, we observed the aggregation of mutant TBP in SCA17 transgenic cerebellar slice and increased ubiquitin signal around Purkinje cells. We found that Purkinje cell survival increased and the ubiquitin signal decreased in the slice culture after cucumin treatment for 5 days. These results reveal that curcumin might have potential in neuron protection.
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Yang, Shu-Ting, and 楊淑婷. "In vitro compound screening for SCA17 and interaction analysis between expanded TBP and HMGB1." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/62117075451669514573.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
98
Neurodegenerative diseases such as hereditary spinocerebellar ataxias (SCAs) type 1, 2, 3, 6, 7, 17 and Huntington's disease are linked to abnormally expanded polyglutamine (polyQ) tract in the respective proteins. The polyQ expansions cause a conformational change in the polypeptide to promote misfolding and aggregation of the disease protein. The expanded polyQ protein may also acquire a toxic function through aberrant protein interactions. The disease-causing gene in SCA17 has been identified as polyQ expansion in the TATA-box binding protein (TBP) gene. TBP is a transcription initiation factor. TBP interacts with other protein factors to regulate gene expression. PolyQ length in TBP N terminal domain ranges from 25~42 in normal population and 43~66 in SCA17. The first aim of this study is to investigate if the polyQ expansion affects HMGB1 binding. By using quartz crystal microbalance (QCM) and GST pull down assay, both E. coli and HEK293T expressed proteins were used to study the interactions between HMGB1 and TBP carrying 20~61 polyQ tract. The results suggest the negative association of polyQ length and HMGB1-TBP interaction. The in vivo length-dependent negative association between TBP and HMGB1 interaction was also suggested by co-expression and co-immunoprecipitation. The second aim of this study is to screen effective chemical compounds which may inhibit polyQ aggregation using thioflavin T binding assay. Among the 31 compounds examined, none displayed effective aggregation inhibition as compared to congo red.
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Wu, Tzu-Ling, and 吳紫綾. "Evaluation of the effects of Chinese herbs on SCA17 through transgenic mouse cerebellar primary culture." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/27123804578326169574.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
100
Spinocerebellar ataxia (SCA) is a complex group of heterogeneous autosomal dominant neurodegenerative disease. The main clinical symptoms in patients consist of ataxia, dystonia, parkinsonism, dementia and seizures, and with a significant cerebellum atrophy in pathology. Many SCAs are caused by the trinucleotide expansion of disease-causing genes. Spinocerebellar ataxia type 17 (SCA17) is resulted from CAG repeat expansion of TBP gene, which encodes polyglutamine (polyQ) stretch in mutant TBP protein. Pathological studies have observed neuron loss in cerebella of patients and hTBP transgenic mice. To study the early pathogenesis and screen potential Chinese herbs for SCA17, we have established a primary culture system from the transgenic mouse cerebella. In the cerebellar primary culture, we observed approximately 70% NeuN positive cells after a long-term culture. That IP3R1 and calbindin positive cells were sustained, revealing this culture system could maintain Purkinje cells survived for more than 4 weeks in vitro. Furthermore, we found that the neurites undergo processing during the culture period, and the reduced processing of SCA17 primary culture can be identified compared to wild-type culture in 6 parameters. In line with expectations, no degenerative cells were observed after 5 days in vitro, however, significant degeneration could be identified in transgenic culture after 14 and 21 days. In addition, severe aggregation was formed in SCA17 primary culture at day 21, which was later than the neurite degeneration. We suggest that aggregation may not an initial event but a late stage symptom of degeneration. We further applied G-CSF to this primary culture to confirm that this system was an appropriate platform for drug screening. Finally, with this culture system, we have evaluated several Chinese herbs and found NH-003 and NH-015 could be potential in neuronal protection. In summary, we have established the SCA17 cerebellar primary culture and which could be a system to study the pathogenesis and screen potential treatments for SCA17.
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Chen, Shiang-Wen, and 陳翔文. "Evaluation of Potential Antioxidative Compounds and Natural Products Using SCA17 Transgenic Mice and Cerebellar Primary Culture." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/70852520173296245081.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
102
Spinocerebellar ataxia 17 (SCA17) is an autosomal dominant neurodegenerative disease caused by trinucleotide CAA/CAG repeat excessive expansion in TATA box Binding Protein (TBP) gene. Expanded CAA/CAG repeat encodes polyglutamine (polyQ) in TBP, which causes mutant polyQ proteins aggregate and the cerebellar Purkinje cell degeneration. Some effective treatments for neurodegenerative disease using Chinese herbs and anti-oxidants have been reported in cellular and animal studies. Our lab has generated SCA17 mouse model and used for potential therapeutic screening. We first used SCA17 transgenic mouse cerebellar primary to screen potential Chinese herbs and anti-oxidative compounds. Immunocytochemistry was conducted to stain Purkinje cell, and measured neurite outgrowth to evaluate the effect of treatment in cerebellar primary culture. The screening results showed two herbal extracts and three synthesized anti-oxidative compounds could increase neurite outgrowth on SCA17 cerebellar primary culture. In vivo treatment results showed that mouse body weight and spontaneous activity were unaffected under the treatment of anti-oxdative compounds. The motor coordination of mice on rotarod task was improved after treatment. We also found that heat shock proteins and superoxide dismutase were increased and Purkinje cell degeneration , mutant protein TBP aggregation and inflammation were attenuated after the treatment with these compounds. These anti-oxidative compounds have potential for SCA17 diseases treatment.
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Rentschler, Alexander [Verfasser]. "Mutationsanalyse des PRKCG-(SCA14) und FGF14-Genes(SCA27) mittels dHPLC bei Ataxie-Patienten / vorgelegt von Alexander Rentschler." 2010. http://d-nb.info/1003207723/34.
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Chen, Zhi-Zhong, and 陳執中. "Evaluation of the efficacy of trehalose through the mouse cerebellar organotypic slice culture and SCA17 transgenic mice." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/68730809819453175086.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
101
Spinocerebellar ataxia (SCA) is an autosomal dominant and progressive neurodegenerative disease chartered by ataxia, parkinsonism, dementia and seizures. Although there remains lots unclarified mechanism in SCA17, it is believed that the mutation on the TATA box binding protein (TBP) is responsible for the disease. The CAG repeat expansion of TBP gene leads to the reduced solubility of polyglutamine (polyQ) TBP and induces aggregate formation. For TBP plays an important role in transcription initiation, the abnormal aggregate is believed to cause neuron degeneration especially in the cerebellar Purkinje cells. Cerebellar organotypic culture is a system which could provide research evidence on tissue level. In addition, the cerebellar organotypic culture could provide the normal interaction between Purkinje cells and the other cells in vitro. We have established this system to study and monitor the cerebellar cell development, neuron survival, Purkinje cell aggregate forming and death and for a drug screening platform. Trehalose is reported to prevent protein degradation and aggregate formation in several disease models, including Huntington’s diseases, Alzheimer's disease, SCA14 and some other neurodegenerative diseases caused by polyQ expansion. In this study, we evaluated the therapeutic effect of trehalose using SCA17 cerebellar organotypic culture system. Our results showed that TBP aggregation formed in the Purkinje cells at in vitro day 3 (DIV3) and became more obvious at DIV7 in the SCA17 cerebellar slice culture. Furthermore, we found that the TBP aggregation significant decreased in our slice culture at DIV7 after treatment with trehalose. To identify the effect of trehalose in vivo, trehalose supplied in the drinking water of SCA17 transgenic mice was conducted. In the behavior test, we found that mice drinking trehalose ameliorated their hyperactivity and improved their coordination in rotarod test. Furthermore, we confirmed that the calbindin expression level was upregulated in the trehalose treatment mouse cerebellum. In addition, the cerebellum size in trehalose treatment mouse is bigger than that of vehicle treatment mouse. In our 4% trehalose treatment study, we found the gait behavior and motor coordination of SCA17 mice were rescued in the footprint and rotarod task, respectively. We also could observe the astrocyte gliosis performance was downregulated after trehalose treatment. However, the microglia cell was activated especially in transgenic trehalose treatment group. Furthermore, the MnSOD was also upregulated after trehalose treatment. These data suggest that trehalose could be a potential non-toxic treatment for SCA17.
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FL, Chen. "Genetic testing of spinocerebellar ataxia types 2 and 17 and oxidative stress study of lymphoblastoid cells with SCA17 TBP expansion." 2005. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0021-2004200714341407.
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Lin, Pei-Ying, and 林佩瑛. "Spinocerebellar ataxia type 17: genetic testing and oxidative stress and cytotoxicity studies using SCA17 lymphoblastoid and HEK-293 cell models." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/6cxxe9.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
96
Spinocerebellar ataxia 17 (SCA17) is an inherited progressive neurodegenerative disease. It is caused by an expanded polyglutamine (polyQ) tract in the TATA-box binding protein (TBP), a general transcription initiation factor, which is crucial for most gene transcription. The expanded polyQ causes a conformational change leading to protein misfolding and aggregation. However, it remains unclear how the polyQ tract affects cellular protein function and induces selective loss of neurons. In this study, we examined the CAG/CAA repeat size range in TBP allele in Taiwanese control subjects and in patients with Parkinson’s disease, essential tremor, and other neurological disorders by SCA17 genotyping. The most common TBP allele contains 36 repeats and two expanded (44 and 45 repeats) alleles were found in patients with OPMD and TICS. Using age- and gender-matched lymphoblastoid and stably induced HEK-293 cells with expanded polyQ, we examined the roles of oxidative stress and chaperones in the pathogenesis of SCA17. In both cell models the relative cell death ratio in cells expressed expanded TBP is significantly higher than that in cells expressed normal TBP upon prooxidant TBH (tert-butyl hydroperoxide) treatment. The results suggest that oxidative stress may be involved in SCA17 pathogenesis. In addition, altered HSPA8 and HSPB1 expressions were observed in lymphoblastoid model or stably induced HEK-293 model, suggesting that HSPA8 and HSPB1 may be involved in SCA17 pathogenesis. Finally, the finding that treatment of histone deacetylases inhibitor valproate increases the viability of cells expressing expanded TBP may help to identify potential targets of SCA17 therapies.
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Lee, Li-Ching, and 李麗卿. "Spinocerebellar ataxia 17 (SCA17) pathogenic mechanisms: Chaperones function and misfolding proteins caused by the expanded polyglutamine in TATA-binding protein." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/u5fc7c.
Full textAbstract:
博士國立臺灣師範大學
生命科學研究所
97
Abstract Expansion of the CAG repeat of the TATA-box binding protein (TBP) gene has been identified as the causative mutations in spinocerebellar ataxia 17 (SCA17). TBP is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The underlying molecular changes of SCA17 are rarely explored. To study the molecular mechanisms underlying SCA17, transient overexpressed and stably induced isogenic 293 cells expressing normal TBP-Q36 and expanded TBP-Q61 were generated and analyzed the expressed proteins using two-dimensional difference in gel electrophoresis (2D-DIGE), followed by mass spectrometry and immunoblotting. Upon induction with doxycycline, the expanded TBP-Q61 formed aggregates with significant increase in cleaved caspase-3. Proteomics study identified a total of 23 proteins with expression changes greater than 1.35 fold. The altered expression of HSPA5, HSPA8 and PARK7 were further validated by 2D and Western immunoblot analyses. In lymphoblastoid cells, significant lower HSPA5, HSPA8 and HSPB1 expression levels were observed in cells with expanded TBP than that of the control cells. Using lentiviral transduced human neuroblastoma cell models, the effects of geldanamycin on HSPA5 expression and SCA17 phenotype were assessed. Genetic screening of triplet expansion in the TBP gene in Taiwanese Parkinson's disease, Alzheimer's disease and atypical parkinsonism revealed a total of 6 expanded alleles (44 ~ 46) in patients group. Reports of additional patients are crucial for better understanding the nature of the disease. Together, this study illustrates the utility of proteomics to identify alterations of proteins which may shed insights into the pathogenesis and lead to therapeutic interventions for this disease.
49
Chen, FL, and 陳玢璘. "Genetic testing of spinocerebellar ataxia types 2 and 17 and oxidative stress study of lymphoblastoid cells with SCA17 TBP expansion." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/33405056709558036661.
Full textAbstract:
碩士國立臺灣師範大學
生命科學研究所
94
Abstract Spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders characterized by cerebellar dysfunction alone or in combination with other neurological abnormalities. Among them, both SCA2 and SCA17 were caused by the expansions of coded CAG trinucleotide repeats. The chromosome 6q27 SCA17 gene encodes a transcription initiation factor TATA-box binding protein (TBP). In this study, SCA2 and SCA17 genotyping was performed to set up the repeat size range in Taiwanese control subjects and in patients with ataxia, dementia, PD, schizophrenia, and other neurological disorders. For SCA2, one borderline (32 repeats) and four pathogenic (35, 40, 48, and 49 repeats) alleles were observed in patients group. For SCA17, no pathogenic expansion was found, but five borderline alleles (44~46 repeats) were found in patients group. To investigate the pathogenic mechanisms underlying the disease, EBV-transformed lymphoblastoid cells from controls and patients with SCA17 TBP expansions were established. Constructs with 3~61 CAG repeat-containing TBP cDNA were also prepared and expressed in SK-N-SK cells to assess the oxidative tolerance of cells upon exposure to t-butylhydroperoxide (TBH). By quantifying the cell viability and the amount of SOD upon TBH treatment, the cells expressed expanded TBP were shown to be more vulnerable to TBH than the cells expressed normal TBP. Quantitative proteomics was used to compare the overall protein expressions among lymphoblastoid cells from SCA17 patients and normal controls. So far, some heat shock factors and oxidative stress related proteins have been suggested from the peer results.
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Kraus, Ondřej. "Existují sekvenční determinanty funkční divergence GTPáz?" Master's thesis, 2013. http://www.nusl.cz/ntk/nusl-321143.
Full textAbstract:
Small GTPases are important proteins that affect many cellular processes. In my work I compare the five most important protein families of small GTPases - Arf, Rab, Ran, Ras and Rho to identify amino acids responsible for major functional differences between different protein families. To compare them, I have used the structural data from the PDB database and sequences from the UniProt database. I have discovered previously undescribed groups of amino acids specific for each protein family of small GTPases with the help of programs ConSurf and Sca5. I also carried out a pilot study of the applicability of B-factors as indicators of bond strength in the protein structure on the example of small GTPases. The first results are not entirely conclusive, but they do not exclude the applicability of B-factors as indicators of bond strength either. Powered by TCPDF (www.tcpdf.org)