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1
Polak, Urszula, Elizabeth McIvor, Sharon Y. R. Dent, Robert D. Wells, and Marek Napierala. "Expanded complexity of unstable repeat diseases." BioFactors 39, no. 2 (December 11, 2012): 164–75. http://dx.doi.org/10.1002/biof.1060.
Повний текст джерела
2
Yang, Su, Huiming Yang, Luoxiu Huang, Luxiao Chen, Zhaohui Qin, Shihua Li, and Xiao-Jiang Li. "Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice." Proceedings of the National Academy of Sciences 117, no. 8 (February 6, 2020): 4411–17. http://dx.doi.org/10.1073/pnas.1919197117.
Повний текст джерелаАнотація:
Identification of repeat-associated non-AUG (RAN) translation in trinucleotide (CAG) repeat diseases has led to the emerging concept that CAG repeat diseases are caused by nonpolyglutamine products. Nonetheless, the in vivo contribution of RAN translation to the pathogenesis of CAG repeat diseases remains elusive. Via CRISPR/Cas9-mediated genome editing, we established knock-in mouse models that harbor expanded CAG repeats in the mouse huntingtin gene to express RAN-translated products with or without polyglutamine peptides. We found that RAN translation is not detected in the knock-in mouse models when expanded CAG repeats are expressed at the endogenous level. Consistently, the expanded CAG repeats that cannot be translated into polyglutamine repeats do not yield the neuropathological and behavioral phenotypes that were found in knock-in mice expressing expanded polyglutamine repeats. Our findings suggest that RAN-translated products do not play a major role in the pathogenesis of CAG repeat diseases and underscore the importance in targeting polyglutamine repeats for therapeutics.
3
Fujino, Yuzo, and Yoshitaka Nagai. "The molecular pathogenesis of repeat expansion diseases." Biochemical Society Transactions 50, no. 1 (December 23, 2021): 119–34. http://dx.doi.org/10.1042/bst20200143.
Повний текст джерелаАнотація:
Expanded short tandem repeats in the genome cause various monogenic diseases, particularly neurological disorders. Since the discovery of a CGG repeat expansion in the FMR1 gene in 1991, more than 40 repeat expansion diseases have been identified to date. In the coding repeat expansion diseases, in which the expanded repeat sequence is located in the coding regions of genes, the toxicity of repeat polypeptides, particularly misfolding and aggregation of proteins containing an expanded polyglutamine tract, have been the focus of investigation. On the other hand, in the non-coding repeat expansion diseases, in which the expanded repeat sequence is located in introns or untranslated regions, the toxicity of repeat RNAs has been the focus of investigation. Recently, these repeat RNAs were demonstrated to be translated into repeat polypeptides by the novel mechanism of repeat-associated non-AUG translation, which has extended the research direction of the pathological mechanisms of this disease entity to include polypeptide toxicity. Thus, a common pathogenesis has been suggested for both coding and non-coding repeat expansion diseases. In this review, we briefly outline the major pathogenic mechanisms of repeat expansion diseases, including a loss-of-function mechanism caused by repeat expansion, repeat RNA toxicity caused by RNA foci formation and protein sequestration, and toxicity by repeat polypeptides. We also discuss perturbation of the physiological liquid-liquid phase separation state caused by these repeat RNAs and repeat polypeptides, as well as potential therapeutic approaches against repeat expansion diseases.
4
Loureiro, Joana R., Ana F. Castro, Ana S. Figueiredo, and Isabel Silveira. "Molecular Mechanisms in Pentanucleotide Repeat Diseases." Cells 11, no. 2 (January 8, 2022): 205. http://dx.doi.org/10.3390/cells11020205.
Повний текст джерелаАнотація:
The number of neurodegenerative diseases resulting from repeat expansion has increased extraordinarily in recent years. In several of these pathologies, the repeat can be transcribed in RNA from both DNA strands producing, at least, one toxic RNA repeat that causes neurodegeneration by a complex mechanism. Recently, seven diseases have been found caused by a novel intronic pentanucleotide repeat in distinct genes encoding proteins highly expressed in the cerebellum. These disorders are clinically heterogeneous being characterized by impaired motor function, resulting from ataxia or epilepsy. The role that apparently normal proteins from these mutant genes play in these pathologies is not known. However, recent advances in previously known spinocerebellar ataxias originated by abnormal non-coding pentanucleotide repeats point to a gain of a toxic function by the pathogenic repeat-containing RNA that abnormally forms nuclear foci with RNA-binding proteins. In cells, RNA foci have been shown to be formed by phase separation. Moreover, the field of repeat expansions has lately achieved an extraordinary progress with the discovery that RNA repeats, polyglutamine, and polyalanine proteins are crucial for the formation of nuclear membraneless organelles by phase separation, which is perturbed when they are expanded. This review will cover the amazing advances on repeat diseases.
5
Eyk, Clare L. van, Saumya E. Samaraweera, Andrew Scott, Dani L. Webber, David P. Harvey, Olivia Mecinger, Louise V. O’Keefe, et al. "Non-self mutation: double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases." Human Molecular Genetics 28, no. 18 (May 9, 2019): 3000–3012. http://dx.doi.org/10.1093/hmg/ddz096.
Повний текст джерелаАнотація:
Abstract Inflammation is activated prior to symptoms in neurodegenerative diseases, providing a plausible pathogenic mechanism. Indeed, genetic and pharmacological ablation studies in animal models of several neurodegenerative diseases demonstrate that inflammation is required for pathology. However, while there is growing evidence that inflammation-mediated pathology may be the common mechanism underlying neurodegenerative diseases, including those due to dominantly inherited expanded repeats, the proximal causal agent is unknown. Expanded CAG.CUG repeat double-stranded RNA causes inflammation-mediated pathology when expressed in Drosophila. Repeat dsRNA is recognized by Dicer-2 as a foreign or ‘non-self’ molecule triggering both antiviral RNA and RNAi pathways. Neither of the RNAi pathway cofactors R2D2 nor loquacious are necessary, indicating antiviral RNA activation. RNA modification enables avoidance of recognition as ‘non-self’ by the innate inflammatory surveillance system. Human ADAR1 edits RNA conferring ‘self’ status and when co-expressed with expanded CAG.CUG dsRNA in Drosophila the pathology is lost. Cricket Paralysis Virus protein CrPV-1A is a known antagonist of Argonaute-2 in Drosophila antiviral defense. CrPV-1A co-expression also rescues pathogenesis, confirming anti-viral-RNA response. Repeat expansion mutation therefore confers ‘non-self’ recognition of endogenous RNA, thereby providing a proximal, autoinflammatory trigger for expanded repeat neurodegenerative diseases.
6
Maritska, Ziske, Baharudin Baharudin, Ardy Santosa, Ching Leng Kee, Tan Yue Ming, and Sultana MH Faradz. "Screening A Trinucleotide Repeat Expansion: How precise PCR can be?" Bioscientia Medicina : Journal of Biomedicine and Translational Research 3, no. 3 (August 31, 2019): 34–40. http://dx.doi.org/10.32539/bsm.v3i3.94.
Повний текст джерелаАнотація:
ABSTRACT
Background. Trinucleotide Repeat Expansion (TRE) in human DNA could lead to various diseases. An expanded CAG repeat (>31 or 37 repeats, depends on the ethnicity) in Androgen Receptor gene is suggested to be associated with the occurrence of isolated hypospadias. In an effort to identify the exact numbers of repeats, sequencing has been the most favored method to be conducted despite its cost.
Objective. This study wished to investigate the possibilities of using Polymerase Chain Reaction (PCR) method to screen expanded repeats in isolated hypospadias, as one of the TRE diseases.
Materials and Methods. Numbers of CAG repeat in twelve hypospadias patients and one normal male was first predicted from the visualization of PCR products in 3% agarose gel electrophoreses with 20 bp ladder marker before it was finally sequenced.
Results. Two samples gave the same exact result, while the rest showed a range of 1-11 bp differences. Statistically, there was a significant difference between the mean of CAG repeats from PCR method (M=26.1667, SD=6.71272) and the mean of CAG repeats from sequencing (M=23.75, SD=5.70685); t(11)= 4.570, p=0.001. Furthermore, the sensitivity of PCR was 100% and the specificity was 83.33%.
Conclusion. It can be concluded that PCR method could be used as a screening method in identifying TRE with large numbers of repeats. However, PCR in TRE disease with small numbers of expanded repeats needs to be followed by sequencing in order to obtain the exact numbers of repeats.
Keywords: Trinucleotide Repeat Expansion, Polymerase Chain Reaction, Sequencing, Isolated Hypospadias
7
O'Donovan, M. C., C. Guy, N. Craddock, T. Bowen, P. McKeon, A. Macedo, W. Maier, et al. "Confirmation of association between expanded CAG/CTG repeats and both schizophrenia and bipolar disorder." Psychological Medicine 26, no. 6 (November 1996): 1145–53. http://dx.doi.org/10.1017/s0033291700035868.
Повний текст джерелаАнотація:
SynopsisRecent studies have suggested that expanded CAG/CTG repeats contribute to the genetic aetiology of schizophrenia and bipolar disorder. However, the nature of this contribution is uncertain and difficult to predict from other known trinucleotide repeat diseases that display much simpler patterns of inheritance. We have sought to replicate and extend earlier findings using Repeat Expansion Detection in an enlarged sample of 152 patients with schizophrenia, 143 patients with bipolar disorder, and 160 controls. We have also examined DNA from the parents of 62 probands with schizophrenia or bipolar disorder. Our results confirm our earlier, preliminary findings of an association between expanded trinucleotide repeats and both schizophrenia and bipolar disorder. However, our data do not support the hypothesis that trinucleotide repeat expansion can alone explain the complex patterns of inheritance of the functional psychoses neither can this mechanism fully explain apparent anticipation.
8
Gleason, Alec C., Ghanashyam Ghadge, Jin Chen, Yoshifumi Sonobe, and Raymond P. Roos. "Machine learning predicts translation initiation sites in neurologic diseases with nucleotide repeat expansions." PLOS ONE 17, no. 6 (June 1, 2022): e0256411. http://dx.doi.org/10.1371/journal.pone.0256411.
Повний текст джерелаАнотація:
A number of neurologic diseases associated with expanded nucleotide repeats, including an inherited form of amyotrophic lateral sclerosis, have an unconventional form of translation called repeat-associated non-AUG (RAN) translation. It has been speculated that the repeat regions in the RNA fold into secondary structures in a length-dependent manner, promoting RAN translation. Repeat protein products are translated, accumulate, and may contribute to disease pathogenesis. Nucleotides that flank the repeat region, especially ones closest to the initiation site, are believed to enhance translation initiation. A machine learning model has been published to help identify ATG and near-cognate translation initiation sites; however, this model has diminished predictive power due to its extensive feature selection and limited training data. Here, we overcome this limitation and increase prediction accuracy by the following: a) capture the effect of nucleotides most critical for translation initiation via feature reduction, b) implement an alternative machine learning algorithm better suited for limited data, c) build comprehensive and balanced training data (via sampling without replacement) that includes previously unavailable sequences, and d) split ATG and near-cognate translation initiation codon data to train two separate models. We also design a supplementary scoring system to provide an additional prognostic assessment of model predictions. The resultant models have high performance, with ~85–88% accuracy, exceeding that of the previously published model by >18%. The models presented here are used to identify translation initiation sites in genes associated with a number of neurologic repeat expansion disorders. The results confirm a number of sites of translation initiation upstream of the expanded repeats that have been found experimentally, and predict sites that are not yet established.
9
Gorbunova, Vera, Andrei Seluanov, Vincent Dion, Zoltan Sandor, James L. Meservy, and John H. Wilson. "Selectable System for Monitoring the Instability of CTG/CAG Triplet Repeats in Mammalian Cells." Molecular and Cellular Biology 23, no. 13 (July 1, 2003): 4485–93. http://dx.doi.org/10.1128/mcb.23.13.4485-4493.2003.
Повний текст джерелаАнотація:
ABSTRACT Despite substantial progress in understanding the mechanism by which expanded CTG/CAG trinucleotide repeats cause neurodegenerative diseases, little is known about the basis for repeat instability itself. By taking advantage of a novel phenomenon, we have developed a selectable assay to detect contractions of CTG/CAG triplets. When inserted into an intron in the APRT gene or the HPRT minigene, long tracts of CTG/CAG repeats (more than about 33 repeat units) are efficiently incorporated into mRNA as a new exon, thereby rendering the encoded protein nonfunctional, whereas short repeat tracts do not affect the phenotype. Therefore, contractions of long repeats can be monitored in large cell populations, by selecting for HPRT+ or APRT+ clones. Using this selectable system, we determined the frequency of spontaneous contractions and showed that treatments with DNA-damaging agents stimulate repeat contractions. The selectable system that we have developed provides a versatile tool for the analysis of CTG/CAG repeat instability in mammalian cells. We also discuss how the effect of long CTG/CAG repeat tracts on splicing may contribute to the progression of polyglutamine diseases.
10
Zhao, Xiaonan, Daman Kumari, Carson J. Miller, Geum-Yi Kim, Bruce Hayward, Antonia G. Vitalo, Ricardo Mouro Pinto, and Karen Usdin. "Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease." Journal of Huntington's Disease 10, no. 1 (February 9, 2021): 149–63. http://dx.doi.org/10.3233/jhd-200423.
Повний текст джерелаАнотація:
Huntington’s disease (HD) is one of a large group of human disorders that are caused by expanded DNA repeats. These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.
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Mizuguchi, Takeshi, Tomoko Toyota, Satoko Miyatake, Satomi Mitsuhashi, Hiroshi Doi, Yosuke Kudo, Hitaru Kishida, et al. "Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment." Brain 144, no. 4 (April 1, 2021): 1103–17. http://dx.doi.org/10.1093/brain/awab021.
Повний текст джерелаАнотація:
Abstract A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype–phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype–phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.
12
Rubinsztein, David C., Bill Amos, and Gillian Cooper. "Microsatellite and trinucleotide-repeat evolution: evidence for mutational bias and different rates of evolution in different lineages." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, no. 1386 (June 29, 1999): 1095–99. http://dx.doi.org/10.1098/rstb.1999.0465.
Повний текст джерелаАнотація:
Microsatellites are stretches of repetitive DNA, where individual repeat units comprise one to six bases. These sequences are often highly polymorphic with respect to repeat number and include trinucleotide repeats, which are abnormally expanded in a number of diseases. It has been widely assumed that microsatellite loci are as likely to gain and lose repeats when they mutate. In this review, we present population genetic and empirical data arguing that microsatellites, including normal alleles at trinucleotide repeat disease loci, are more likely to expand in length when they mutate. In addition, our experiments suggest that the rates of expansion of such sequences differ in related species.
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DeJesus-Hernandez, Mariely, Ross A. Aleff, Jazmyne L. Jackson, NiCole A. Finch, Matthew C. Baker, Tania F. Gendron, Melissa E. Murray, et al. "Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases." Brain 144, no. 4 (April 1, 2021): 1082–88. http://dx.doi.org/10.1093/brain/awab006.
Повний текст джерелаАнотація:
Abstract To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10−4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10− 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.
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Jarjanazi, Hamdi, Hong Li, Irene L. Andrulis, and Hilmi Ozcelik. "Genome Wide Screening of CAG Trinucleotide Repeat Lengths in Breast Cancer." Disease Markers 22, no. 5-6 (2006): 343–49. http://dx.doi.org/10.1155/2006/951857.
Повний текст джерелаАнотація:
Trinucleotide repeat sequences are widely present in the human genome. The expansion of CAG repeats have been studied very extensively, and shown to be the causative mechanism of more than 40 neuromuscular and neurodegenerative diseases. In the present study, we performed a genome wide screening of CAG repeat expansions in non-neoplastic tissues of 212 breast cancer cases and 196 healthy population controls using the Repeat Expansion Detection (RED) method. Distribution of CAG repeat lengths in cases was not significantly different from controls. However, dramatically expanded CAG repeats were detected in 2.4% (n= 5) of breast cancer cases where no repeats of similar size were detected in any of the healthy population controls. Although this trend shows only borderline significance (p= 0.06), this finding suggests a potential involvement of CAG repeat expansion in breast cancer susceptibility. These repeats may potentially affect the function of cancer predisposition genes, with a similar mechanism as in neurodegenerative and neuromuscular disorders.
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Su, Xiaofeng A., and Catherine H. Freudenreich. "Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae." Proceedings of the National Academy of Sciences 114, no. 40 (September 18, 2017): E8392—E8401. http://dx.doi.org/10.1073/pnas.1711283114.
Повний текст джерелаАнотація:
CAG/CTG repeats are structure-forming repetitive DNA sequences, and expansion beyond a threshold of ∼35 CAG repeats is the cause of several human diseases. Expanded CAG repeats are prone to breakage, and repair of the breaks can cause repeat contractions and expansions. In this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast chromosome. R-loops were further elevated upon deletion of yeast RNaseH genes and caused repeat fragility. A significant increase in CAG repeat contractions was also observed, consistent with previous human cell studies. Deletion of yeast cytosine deaminase Fcy1 significantly decreased the rate of CAG repeat fragility and contractions in the rnh1Δrnh201Δ background, indicating that Fcy1-mediated deamination is one cause of breakage and contractions in the presence of R-loops. Furthermore, base excision repair (BER) is responsible for causing CAG repeat contractions downstream of Fcy1, but not fragility. The Rad1/XPF and Rad2/XPG nucleases were also important in protecting against contractions, but through BER rather than nucleotide excision repair. Surprisingly, the MutLγ (Mlh1/Mlh3) endonuclease caused R-loop–dependent CAG fragility, defining an alternative function for this complex. These findings provide evidence that breakage at expanded CAG repeats occurs due to R-loop formation and reveal two mechanisms for CAG repeat instability: one mediated by cytosine deamination of DNA engaged in R-loops and the other by MutLγ cleavage. Since disease-causing CAG repeats occur in transcribed regions, our results suggest that R-loop–mediated fragility is a mechanism that could cause DNA damage and repeat-length changes in human cells.
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Johnson, Sean L., Matthew V. Prifti, Alyson Sujkowski, Kozeta Libohova, Jessica R. Blount, Luke Hong, Wei-Ling Tsou, and Sokol V. Todi. "Drosophila as a Model of Unconventional Translation in Spinocerebellar Ataxia Type 3." Cells 11, no. 7 (April 4, 2022): 1223. http://dx.doi.org/10.3390/cells11071223.
Повний текст джерелаАнотація:
RNA toxicity contributes to diseases caused by anomalous nucleotide repeat expansions. Recent work demonstrated RNA-based toxicity from repeat-associated, non-AUG-initiated translation (RAN translation). RAN translation occurs around long nucleotide repeats that form hairpin loops, allowing for translation initiation in the absence of a start codon that results in potentially toxic, poly-amino acid repeat-containing proteins. Discovered in Spinocerebellar Ataxia Type (SCA) 8, RAN translation has been documented in several repeat-expansion diseases, including in the CAG repeat-dependent polyglutamine (polyQ) disorders. The ATXN3 gene, which causes SCA3, also known as Machado–Joseph Disease (MJD), contains a CAG repeat that is expanded in disease. ATXN3 mRNA possesses features linked to RAN translation. In this paper, we examined the potential contribution of RAN translation to SCA3/MJD in Drosophila by using isogenic lines that contain homomeric or interrupted CAG repeats. We did not observe unconventional translation in fly neurons or glia. However, our investigations indicate differential toxicity from ATXN3 protein-encoding mRNA that contains pure versus interrupted CAG repeats. Additional work suggests that this difference may be due in part to toxicity from homomeric CAG mRNA. We conclude that Drosophila is not suitable to model RAN translation for SCA3/MJD, but offers clues into the potential pathogenesis stemming from CAG repeat-containing mRNA in this disorder.
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Zhao, Xiaonan, and Karen Usdin. "(Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology in FMR1 Disorders." International Journal of Molecular Sciences 22, no. 17 (August 25, 2021): 9167. http://dx.doi.org/10.3390/ijms22179167.
Повний текст джерелаАнотація:
Fragile X-related disorders (FXDs), also known as FMR1 disorders, are examples of repeat expansion diseases (REDs), clinical conditions that arise from an increase in the number of repeats in a disease-specific microsatellite. In the case of FXDs, the repeat unit is CGG/CCG and the repeat tract is located in the 5′ UTR of the X-linked FMR1 gene. Expansion can result in neurodegeneration, ovarian dysfunction, or intellectual disability depending on the number of repeats in the expanded allele. A growing body of evidence suggests that the mutational mechanisms responsible for many REDs share several common features. It is also increasingly apparent that in some of these diseases the pathologic consequences of expansion may arise in similar ways. It has long been known that many of the disease-associated repeats form unusual DNA and RNA structures. This review will focus on what is known about these structures, the proteins with which they interact, and how they may be related to the causative mutation and disease pathology in the FMR1 disorders.
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Lawlor, Kynan T., Louise V. O'Keefe, Saumya E. Samaraweera, Clare L. van Eyk, Catherine J. McLeod, Christopher A. Maloney, Thurston H. Y. Dang, Catherine M. Suter, and Robert I. Richards. "Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neurodegenerative diseases." Human Molecular Genetics 20, no. 19 (June 30, 2011): 3757–68. http://dx.doi.org/10.1093/hmg/ddr292.
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Lieberman, Andrew P., Vikram G. Shakkottai, and Roger L. Albin. "Polyglutamine Repeats in Neurodegenerative Diseases." Annual Review of Pathology: Mechanisms of Disease 14, no. 1 (January 24, 2019): 1–27. http://dx.doi.org/10.1146/annurev-pathmechdis-012418-012857.
Повний текст джерелаАнотація:
Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.
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Joachimiak, Paweł, Adam Ciesiołka, Grzegorz Figura, and Agnieszka Fiszer. "Implications of Poly(A) Tail Processing in Repeat Expansion Diseases." Cells 11, no. 4 (February 15, 2022): 677. http://dx.doi.org/10.3390/cells11040677.
Повний текст джерелаАнотація:
Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- to dodeca-nucleotide-long units. Mutant mRNA is a pathogenic factor or important contributor to the disease and has great potential as a therapeutic target. Although repeat expansion diseases are quite well known, there are limited studies concerning polyadenylation events for implicated transcripts that could have profound effects on transcript stability, localization, and translation efficiency. In this review, we briefly present polyadenylation and alternative polyadenylation (APA) mechanisms and discuss their role in the pathogenesis of selected diseases. We also discuss several methods for poly(A) tail measurement (both transcript-specific and transcriptome-wide analyses) and APA site identification—the further development and use of which may contribute to a better understanding of the correlation between APA events and repeat expansion diseases. Finally, we point out some future perspectives on the research into repeat expansion diseases, as well as APA studies.
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Galka-Marciniak, Paulina, Martyna O. Urbanek, and Wlodzimierz J. Krzyzosiak. "Triplet repeats in transcripts: structural insights into RNA toxicity." Biological Chemistry 393, no. 11 (November 1, 2012): 1299–315. http://dx.doi.org/10.1515/hsz-2012-0218.
Повний текст джерелаАнотація:
Abstract Tandem repeats of various trinucleotide motifs are frequent entities in transcripts, and RNA structures formed by these sequences depend on the motif type and number of reiterations. The functions performed by normal triplet repeats in transcripts are poorly understood, but abnormally expanded repeats of certain types trigger pathogenesis in several human genetic disorders known as the triplet repeat expansion diseases (TREDs). The diseases caused by expanded non-coding CUG and CGG repeats in transcripts include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome. Another group of disorders in which transcripts containing translated CAG repeats play an auxiliary role in pathogenesis include Huntington’s disease and several spinocerebellar ataxias. In this review, we gathered existing knowledge regarding the structural features of triplet repeats in transcripts and discussed this in the context of various pathogenic mechanisms assigned to toxic RNA repeats. These mechanisms include aberrant alternative splicing, the inhibition of nuclear transport and export, induction of the innate immune response, alteration of a microRNA biogenesis pathway and abnormal activation of an RNA interference pathway. We also provide ideas for future investigations to reveal further mechanisms of pathogenesis directly triggered by mutant RNA repeats in TREDs.
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Davies, Philippa, Kate Watt, Sharon M. Kelly, Caroline Clark, Nicholas C. Price, and Iain J. McEwan. "Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain." Journal of Molecular Endocrinology 41, no. 5 (September 1, 2008): 301–14. http://dx.doi.org/10.1677/jme-08-0042.
Повний текст джерелаАнотація:
Poly-amino acid repeats, especially long stretches of glutamine (Q), are common features of transcription factors and cell-signalling proteins and are prone to expansion, resulting in neurodegenerative diseases. The amino-terminal domain of the androgen receptor (AR-NTD) has a poly-Q repeat between 9 and 36 residues, which when it expands above 40 residues results in spinal bulbar muscular atrophy. We have used spectroscopy and biochemical analysis to investigate the structural consequences of an expanded repeat (Q45) or removal of the repeat (ΔQ) on the folding of the AR-NTD. Circular dichroism spectroscopy revealed that in aqueous solution, the AR-NTD has a relatively limited amount of stable secondary structure. Expansion of the poly-Q repeat resulted in a modest increase in α-helix structure, while deletion of the repeat resulted in a small loss of α-helix structure. These effects were more pronounced in the presence of the structure-promoting solvent trifluoroethanol or the natural osmolyte trimethylamine N-oxide. Fluorescence spectroscopy showed that the microenvironments of four tryptophan residues were also altered after the deletion of the Q stretch. Other structural changes were observed for the AR-NTDQ45 polypeptide after limited proteolysis; in addition, this polypeptide not only showed enhanced binding of the hydrophobic probe 8-anilinonaphthalene-1-sulphonic acid but was more sensitive to urea-induced unfolding. Taken together, these findings support the view that the presence and length of the poly-Q repeat modulate the folding and structure of the AR-NTD.
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Donaldson, Jasmine, Sophie Powell, Nadia Rickards, Peter Holmans, and Lesley Jones. "What is the Pathogenic CAG Expansion Length in Huntington’s Disease?" Journal of Huntington's Disease 10, no. 1 (February 9, 2021): 175–202. http://dx.doi.org/10.3233/jhd-200445.
Повний текст джерелаАнотація:
Huntington’s disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. Age at onset of the disease is inversely correlated with the inherited CAG length, but is further modulated by a series of genetic modifiers which are most likely to act on the CAG repeat in HTT that permit it to further expand. Longer repeats are more prone to expansions, and this expansion is age dependent and tissue-specific. Given that the inherited tract expands through life and most subjects develop disease in mid-life, this implies that in cells that degenerate, the CAG length is likely to be longer than the inherited length. These findings suggest two thresholds— the inherited CAG length which permits further expansion, and the intracellular pathogenic threshold, above which cells become dysfunctional and die. This two-step mechanism has been previously proposed and modelled mathematically to give an intracellular pathogenic threshold at a tract length of 115 CAG (95% confidence intervals 70– 165 CAG). Empirically, the intracellular pathogenic threshold is difficult to determine. Clues from studies of people and models of HD, and from other diseases caused by expanded repeat tracts, place this threshold between 60– 100 CAG, most likely towards the upper part of that range. We assess this evidence and discuss how the intracellular pathogenic threshold in manifest disease might be better determined. Knowing the cellular pathogenic threshold would be informative for both understanding the mechanism in HD and deploying treatments.
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Groh, Matthias, Lara Marques Silva, and Natalia Gromak. "Mechanisms of transcriptional dysregulation in repeat expansion disorders." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 1123–28. http://dx.doi.org/10.1042/bst20140049.
Повний текст джерелаАнотація:
Approximately 40 human diseases are associated with expansion of repeat sequences. These expansions can reside within coding or non-coding parts of the genes, affecting the host gene function. The presence of such expansions results in the production of toxic RNA and/or protein or causes transcriptional repression and silencing of the host gene. Although the molecular mechanisms of expansion diseases are not well understood, mounting evidence suggests that transcription through expanded repeats plays an essential role in disease pathology. The presence of an expansion can affect RNA polymerase transcription, leading to dysregulation of transcription-associated processes, such as RNA splicing, formation of RNA/DNA hybrids (R-loops), production of antisense, short non-coding and bidirectional RNA transcripts. In the present review, we summarize current advances in this field and discuss possible roles of transcriptional defects in disease pathology.
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Ninomiya, Kensuke, and Tetsuro Hirose. "Short Tandem Repeat-Enriched Architectural RNAs in Nuclear Bodies: Functions and Associated Diseases." Non-Coding RNA 6, no. 1 (February 20, 2020): 6. http://dx.doi.org/10.3390/ncrna6010006.
Повний текст джерелаАнотація:
Nuclear bodies are membraneless, phase-separated compartments that concentrate specific proteins and RNAs in the nucleus. They are believed to serve as sites for the modification, sequestration, and storage of specific factors, and to act as organizational hubs of chromatin structure to control gene expression and cellular function. Architectural (arc) RNA, a class of long noncoding RNA (lncRNA), plays essential roles in the formation of nuclear bodies. Herein, we focus on specific arcRNAs containing short tandem repeat-enriched sequences and introduce their biological functions and recently elucidated underlying molecular mechanism. In various neurodegenerative diseases, abnormal nuclear and cytoplasmic bodies are built on disease-causing RNAs or toxic RNAs with aberrantly expanded short tandem repeat-enriched sequences. We discuss the possible analogous functions of natural arcRNAs and toxic RNAs with short tandem repeat-enriched sequences. Finally, we describe the technical utility of short tandem repeat-enriched arcRNAs as a model for exploring the structures and functions of nuclear bodies, as well as the pathogenic mechanisms of neurodegenerative diseases.
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Arning, Larissa, and Huu Phuc Nguyen. "Huntington disease update: new insights into the role of repeat instability in disease pathogenesis." Medizinische Genetik 33, no. 4 (December 1, 2021): 293–300. http://dx.doi.org/10.1515/medgen-2021-2101.
Повний текст джерелаАнотація:
Abstract The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.
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Higham, Catherine F., and Darren G. Monckton. "Modelling and inference reveal nonlinear length-dependent suppression of somatic instability for small disease associated alleles in myotonic dystrophy type 1 and Huntington disease." Journal of The Royal Society Interface 10, no. 88 (November 6, 2013): 20130605. http://dx.doi.org/10.1098/rsif.2013.0605.
Повний текст джерелаАнотація:
More than 20 human genetic diseases are associated with inheriting an unstable expanded DNA simple sequence tandem repeat, for example, CTG (cytosine–thymine–guanine) repeats in myotonic dystrophy type 1 (DM1) and CAG (cytosine–adenine–guanine) repeats in Huntington disease (HD). These sequences mutate by changing the number of repeats not just between generations, but also during the lifetime of affected individuals. Levels of somatic instability contribute to disease onset and progression but as changes are tissue-specific, age- and repeat length-dependent, interpretation of the level of somatic instability in an individual is confounded by these considerations. Mathematical models, fitted to CTG repeat length distributions derived from blood DNA, from a large cohort of DM1-affected or at risk individuals, have recently been used to quantify inherited repeat lengths and mutation rates. Taking into account age, the estimated mutation rates are lower than predicted among individuals with small alleles (inherited repeat lengths less than 100 CTGs), suggesting that these rates may be suppressed at the lower end of the disease-causing range. In this study, we propose that a length-specific effect operates within this range and tested this hypothesis using a model comparison approach. To calibrate the extended model, we used data derived from blood DNA from DM1 individuals and, for the first time, buccal DNA from HD individuals. In a novel application of this extended model, we identified individuals whose effective repeat length, with regards to somatic instability, is less than their actual repeat length. A plausible explanation for this distinction is that the expanded repeat tract is compromised by interruptions or other unusual features. We quantified effective length for a large cohort of DM1 individuals and showed that effective length better predicts age of onset than inherited repeat length, thus improving the genotype–phenotype correlation. Under the extended model, we removed some of the bias in mutation rates making them less length-dependent. Consequently, rates adjusted in this way will be better suited as quantitative traits to investigate cis- or trans -acting modifiers of somatic mosaicism, disease onset and progression.
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Stochmanski, Shawn J., François Blondeau, Martine Girard, Pascale Hince, Daniel Rochefort, Claudia Gaspar, Patrick A. Dion, Peter S. McPherson, and Guy A. Rouleau. "A polyalanine antibody for the diagnosis of oculopharyngeal muscular dystrophy and polyalanine-related diseases." MNI Open Research 1 (December 5, 2017): 1. http://dx.doi.org/10.12688/mniopenres.12765.1.
Повний текст джерелаАнотація:
Eighteen severe human diseases have so far been associated with trinucleotide repeat expansions coding for either polyalanine (encoded by a GCN repeat tract) or polyglutamine (encoded by a CAG repeat tract). Among them, oculopharyngeal muscular dystrophy (OPMD), spinocerebellar ataxia type-3 (SCA3), and Huntington’s disease (HD) are late-onset autosomal-dominant disorders characterized by the presence of intranuclear inclusions (INIs). We have previously identified the OPMD causative mutation as a small expansion (from 2 in normal to 7 in disease) of a GCG repeat tract in the PABPN1 gene. In addition, -1 ribosomal frameshifting has been reported to occur in expanded CAG repeat tracts in the ATXN3 (SCA3) and HTT (HD) genes, resulting in the translation of a hybrid CAG/GCA repeat tract and the production of a polyalanine-containing peptide. Previous studies on OPMD suggest that polyalanine-induced toxicity is very sensitive to the dosage and length of the alanine stretch. Here we report the characterization of a polyclonal antibody that selectively recognizes pathological expansions of polyalanine in PABPN1. Furthermore, our antibody also detects the presence of alanine proteins in INIs of SCA3 and HD patient samples.
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Wang, Eric T., Daniel Treacy, Katy Eichinger, Adam Struck, Joseph Estabrook, Hailey Olafson, Thomas T. Wang, et al. "Transcriptome alterations in myotonic dystrophy skeletal muscle and heart." Human Molecular Genetics 28, no. 8 (December 17, 2018): 1312–21. http://dx.doi.org/10.1093/hmg/ddy432.
Повний текст джерелаАнотація:
Abstract Myotonic dystrophy (dystrophia myotonica, DM) is a multi-systemic disease caused by expanded CTG or CCTG microsatellite repeats. Characterized by symptoms in muscle, heart and central nervous system, among others, it is one of the most variable diseases known. A major pathogenic event in DM is the sequestration of muscleblind-like proteins by CUG or CCUG repeat-containing RNAs transcribed from expanded repeats, and differences in the extent of MBNL sequestration dependent on repeat length and expression level may account for some portion of the variability. However, many other cellular pathways are reported to be perturbed in DM, and the severity of specific disease symptoms varies among individuals. To help understand this variability and facilitate research into DM, we generated 120 RNASeq transcriptomes from skeletal and heart muscle derived from healthy and DM1 biopsies and autopsies. A limited number of DM2 and Duchenne muscular dystrophy samples were also sequenced. We analyzed splicing and gene expression, identified tissue-specific changes in RNA processing and uncovered transcriptome changes strongly correlating with muscle strength. We created a web resource at http://DMseq.org that hosts raw and processed transcriptome data and provides a lightweight, responsive interface that enables browsing of processed data across the genome.
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Konopka, Anna, and Julie Atkin. "The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 19, no. 10 (October 12, 2018): 3137. http://dx.doi.org/10.3390/ijms19103137.
Повний текст джерелаАнотація:
Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.
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Sinnreich, Michael, Eric J. Sorenson, and Christopher J. Klein. "Neurologic Course, Endocrine Dysfunction and Triplet Repeat Size in Spinal Bulbar Muscular Atrophy." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 31, no. 3 (August 2004): 378–82. http://dx.doi.org/10.1017/s0317167100003486.
Повний текст джерелаАнотація:
Objective:To study the role of diabetes, gynecomastia and CAG triplet repeat size as disease modifying factors of neurologic expression in spinal bulbar muscular atrophy (SBMA, Kennedy's disease).Methods:Twenty unrelated SBMApatients with confirmatory genetic testing were reviewed. Patterns of neurologic involvement were assessed (e.g. bulbar, asymmetric, proximal, distal, motor and sensory). Slopes of disease progression were calculated from serial quantified neurologic examinations. Patterns of neurologic involvement and course were correlated to the presence of diabetes, gynecomastia and triplet repeat size.Results:Diabetes or glucose impairment occurred in nine and 11 had gynecomastia. Patterns of neurologic involvement and rates of progression did not correlate with these endocrine diseases or triplet repeat sizes. Correlation was seen between number of CAG repeats and age of onset weakness (r = -0.53, r2 = 29%, p = 0.01).Conclusion:The specific neurotoxic effect of expanded CAGs appears limited to age of onset weakness in SBMA. Although significant, only 29% of the variability in onset age could be accounted for by polyglutamine size suggesting the importance of other unidentified factors. In this series diabetes or glucose impairment was more common than previously reported and, like gynecomastia, did not correlate with size of triplet repeats, severity or patterns of neurologic involvement. Modifying factors other than diabetes, gynecomastia or triplet repeat size are suggested in disease expression.
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Kawakubo, Kosuke, Susumu Ikenoshita, Kazuya Matsuo, Sefan Asamitsu, Yasushi Yabuki, Hiroshi Sugiyama, and Norifumi Shioda. "Therapeutic targeting expanded DNA using cyclic pyrrole-imidazole polyamide in CAG/CTG triplet repeat neurological diseases." Proceedings for Annual Meeting of The Japanese Pharmacological Society 95 (2022): 1—SS—27. http://dx.doi.org/10.1254/jpssuppl.95.0_1-ss-27.
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Maduro, Maria Rosa, Roberto Casella, Alex G. Smith, and Dolores J. Lamb. "Increased incidence of triplet repeat diseases expanded alleles in azoospermic men: a new concern for ICSI?" Fertility and Sterility 78 (September 2002): S32. http://dx.doi.org/10.1016/s0015-0282(02)03465-9.
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Mousavi, Nima, Sharona Shleizer-Burko, Richard Yanicky, and Melissa Gymrek. "Profiling the genome-wide landscape of tandem repeat expansions." Nucleic Acids Research 47, no. 15 (June 13, 2019): e90-e90. http://dx.doi.org/10.1093/nar/gkz501.
Повний текст джерелаАнотація:
Abstract Tandem repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington’s Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-generation sequencing (NGS) datasets and are not profiled by existing genome-wide tools. We present GangSTR, a novel algorithm for genome-wide genotyping of both short and expanded TRs. GangSTR extracts information from paired-end reads into a unified model to estimate maximum likelihood TR lengths. We validate GangSTR on real and simulated data and show that GangSTR outperforms alternative methods in both accuracy and speed. We apply GangSTR to a deeply sequenced trio to profile the landscape of TR expansions in a healthy family and validate novel expansions using orthogonal technologies. Our analysis reveals that healthy individuals harbor dozens of long TR alleles not captured by current genome-wide methods. GangSTR will likely enable discovery of novel disease-associated variants not currently accessible from NGS.
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de Pontual, Laure, and Stéphanie Tomé. "Overview of the Complex Relationship between Epigenetics Markers, CTG Repeat Instability and Symptoms in Myotonic Dystrophy Type 1." International Journal of Molecular Sciences 23, no. 7 (March 23, 2022): 3477. http://dx.doi.org/10.3390/ijms23073477.
Повний текст джерелаАнотація:
Among the trinucleotide repeat disorders, myotonic dystrophy type 1 (DM1) is one of the most complex neuromuscular diseases caused by an unstable CTG repeat expansion in the DMPK gene. DM1 patients exhibit high variability in the dynamics of CTG repeat instability and in the manifestations and progression of the disease. The largest expanded alleles are generally associated with the earliest and most severe clinical form. However, CTG repeat length alone is not sufficient to predict disease severity and progression, suggesting the involvement of other factors. Several data support the role of epigenetic alterations in clinical and genetic variability. By highlighting epigenetic alterations in DM1, this review provides a new avenue on how these changes can serve as biomarkers to predict clinical features and the mutation behavior.
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Furtado, Gabriel Vasata, Jing Yang, Di Wu, Christos I. Papagiannopoulos, Hanna M. Terpstra, E. F. Elsiena Kuiper, Sybille Krauss, Wei-Guo Zhu, Harm H. Kampinga, and Steven Bergink. "FOXO1 controls protein synthesis and transcript abundance of mutant polyglutamine proteins, preventing protein aggregation." Human Molecular Genetics 30, no. 11 (April 2, 2021): 996–1005. http://dx.doi.org/10.1093/hmg/ddab095.
Повний текст джерелаАнотація:
Abstract FOXO1, a transcription factor downstream of the insulin/insulin like growth factor axis, has been linked to protein degradation. Elevated expression of FOXO orthologs can also prevent the aggregation of cytosine adenine guanine (CAG)-repeat disease causing polyglutamine (polyQ) proteins but whether FOXO1 targets mutant proteins for degradation is unclear. Here, we show that increased expression of FOXO1 prevents toxic polyQ aggregation in human cells while reducing FOXO1 levels has the opposite effect and accelerates it. Although FOXO1 indeed stimulates autophagy, its effect on polyQ aggregation is independent of autophagy, ubiquitin–proteasome system (UPS) mediated protein degradation and is not due to a change in mutant polyQ protein turnover. Instead, FOXO1 specifically downregulates protein synthesis rates from expanded pathogenic CAG repeat transcripts. FOXO1 orchestrates a change in the composition of proteins that occupy mutant expanded CAG transcripts, including the recruitment of IGF2BP3. This mRNA binding protein enables a FOXO1 driven decrease in pathogenic expanded CAG transcript- and protein levels, thereby reducing the initiation of amyloidogenesis. Our data thus demonstrate that FOXO1 not only preserves protein homeostasis at multiple levels, but also reduces the accumulation of aberrant RNA species that may co-contribute to the toxicity in CAG-repeat diseases.
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RANKIN, Julia, Andreas WYTTENBACH, and David C. RUBINSZTEIN. "Intracellular green fluorescent protein–polyalanine aggregates are associated with cell death." Biochemical Journal 348, no. 1 (May 9, 2000): 15–19. http://dx.doi.org/10.1042/bj3480015.
Повний текст джерелаАнотація:
Eight diseases, exemplified by Huntington's disease and spinocerebellar ataxia type 1, are caused by CAG-repeat expansion mutations. The CAG repeats are translated into expanded polyglutamine tracts, which are associated with deleterious novel functions. While these diseases are characterized by intraneuronal aggregate formation, it is unclear whether the aggregates cause disease. We have addressed this debate by generating intracellular aggregates with green fluorescent protein (GFP) fused to 19-37 alanines. No aggregates were seen in cells expressing native GFP or GFP fused to seven alanines. Aggregate-containing cells expressing GFP fused to 19-37 polyalanines show high rates of nuclear fragmentation compared with cells expressing the same constructs without aggregates, or cells expressing GFP fused to seven alanines. This suggests an association between aggregate formation and cell death.
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Shreen, Sara, Mohammed Baleeqh Uddin, Mir Salman Ali, and Zoha Sultana. "The Role of Antiplatelet agents in ischemic events." Journal of Drug Delivery and Therapeutics 11, no. 4-S (August 15, 2021): 187–94. http://dx.doi.org/10.22270/jddt.v11i4-s.4926.
Повний текст джерелаАнотація:
Antiplatelet treatment could be a key in pharmacological treatment for avoidance of coronary heart disease (CHD) and stroke. Depending on sign, term of antiplatelet monotherapy or double treatment is shifted. Antiplatelet treatment is shown to avoid a repeat of cardiovascular occasion, in any case, expanded term of dual antiplatelet treatment (DAPT) related with expanded hazard of bleeding. Unstable angina happens due to partially or totally block of the blood coronary blood vessel driving to coronary ischaemia. Intense coronary infection happens due to drawn out coronary ischaemia which causes coronary diseases.
Keywords: dual antiplatelet treatment (DAPT), coronary heart disease (CHD) and stroke.
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Matlahov, Irina, and Patrick CA van der Wel. "Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease." Experimental Biology and Medicine 244, no. 17 (June 15, 2019): 1584–95. http://dx.doi.org/10.1177/1535370219856620.
Повний текст джерелаАнотація:
Huntington’s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington’s disease patients and their families, with the disease typically being fatal within 10–15 years from onset. Huntington’s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington’s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington’s disease are found within patients’ neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms. Impact statement Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington’s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.
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Zhang, Nan, and Tetsuo Ashizawa. "Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions." Cells 11, no. 9 (May 6, 2022): 1567. http://dx.doi.org/10.3390/cells11091567.
Повний текст джерелаАнотація:
Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from Alu elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms complex secondary and tertiary structures that can give rise to RNA-mediated toxicity, including protein sequestration, pentapeptide synthesis, and mRNA dysregulation. Since several of these diseases have recently been discovered, our understanding of their pathological mechanisms is limited, and their therapeutic interventions underexplored. This review aims to highlight new in vitro and in vivo insights into these incurable diseases.
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Truant, Ray, Lynn A. Raymond, Jianrun Xia, Deborah Pinchev, Anjee Burtnik, and Randy Singh Atwal. "Canadian Association of Neurosciences Review: Polyglutamine Expansion Neurodegenerative Diseases." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 33, no. 3 (August 2006): 278–91. http://dx.doi.org/10.1017/s031716710000514x.
Повний текст джерелаАнотація:
ABSTRACT:Since the early 1990s, DNA triplet repeat expansions have been found to be the cause in an ever increasing number of genetic neurologic diseases. A subset of this large family of genetic diseases has the expansion of a CAG DNA triplet in the open reading frame of a coding exon. The result of this DNA expansion is the expression of expanded glutamine amino acid repeat tracts in the affected proteins, leading to the term, Polyglutamine Diseases, which is applied to this sub-family of diseases. To date, nine distinct genes are known to be linked to polyglutamine diseases, including Huntington's disease, Machado-Joseph Disease and spinobulbar muscular atrophy or Kennedy's disease. Most of the polyglutamine diseases are characterized clinically as spinocerebellar ataxias. Here we discuss recent successes and advancements in polyglutamine disease research, comparing these different diseases with a common genetic flaw at the level of molecular biology and early drug design for a family of diseases where many new research tools for these genetic disorders have been developed. Polyglutamine disease research has successfully used interdisciplinary collaborative efforts, informative multiple mouse genetic models and advanced tools of pharmaceutical industry research to potentially serve as the prototype model of therapeutic research and development for rare neurodegenerative diseases.
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Raaijmakers, Renée H. L., Lise Ripken, C. Rosanne M. Ausems, and Derick G. Wansink. "CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities." International Journal of Molecular Sciences 20, no. 15 (July 27, 2019): 3689. http://dx.doi.org/10.3390/ijms20153689.
Повний текст джерелаАнотація:
CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with a variable multisystemic character for which no cure is yet available. Here, we review CRISPR/Cas-mediated approaches that target the unstable (CTG•CAG)n repeat in the DMPK/DM1-AS gene pair, the autosomal dominant mutation that causes DM1. Expansion of the repeat results in a complex constellation of toxicity at the DNA level, an altered transcriptome and a disturbed proteome. To restore cellular homeostasis and ameliorate DM1 disease symptoms, CRISPR/Cas approaches were directed at the causative mutation in the DNA and the RNA. Specifically, the triplet repeat has been excised from the genome by several laboratories via dual CRISPR/Cas9 cleavage, while one group prevented transcription of the (CTG)n repeat through homology-directed insertion of a polyadenylation signal in DMPK. Independently, catalytically deficient Cas9 (dCas9) was recruited to the (CTG)n repeat to block progression of RNA polymerase II and a dCas9-RNase fusion was shown to degrade expanded (CUG)n RNA. We compare these promising developments in DM1 with those in other microsatellite instability diseases. Finally, we look at hurdles that must be taken to make CRISPR/Cas-mediated editing a therapeutic reality in patients.
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Coarelli, Giulia, Alhassane Diallo, Morgane Sonia Thion, Daisy Rinaldi, Fabienne Calvas, Ouahid Lagha Boukbiza, Alina Tataru, et al. "Low cancer prevalence in polyglutamine expansion diseases." Neurology 88, no. 12 (February 15, 2017): 1114–19. http://dx.doi.org/10.1212/wnl.0000000000003725.
Повний текст джерелаАнотація:
Objective:Polyglutamine (PolyQ) diseases are dominantly transmitted neurologic disorders, caused by coding and expanded CAG trinucleotide repeats. Cancer was reported retrospectively to be rare in patients with PolyQ diseases and we aimed to investigate its prevalence in France.Methods:Consecutive patients with Huntington disease (HD) and spinocerebellar ataxia (SCA) were questioned about cancer, cardiovascular diseases, and related risk factors in 4 university hospitals in Paris, Toulouse, Strasbourg, and Montpellier. Standardized incidence ratios (SIR), based on age- and sex-adjusted rate of the French population, were assessed for different types of cancer.Results:We questioned 372 patients with HD and 134 patients with SCA. SIR showed significantly reduced risk of cancer in HD: 23 observed cases vs 111.05 expected ones (SIR 0.21, 95% confidence interval [CI] 0.13–0.31), as well as in SCA: 7 observed cases vs 34.73 expected (SIR 0.23, 95% CI 0.08–0.42). This was surprising since risk behavior for cancer was increased in these patients, with significantly greater tobacco and alcohol consumption in patients with HD vs patients with SCA (p < 0.0056). There was no association between CAG repeat size and cancer or cardiovascular disease. However, in patients with HD, skin cancers were more frequent than expected (5 vs 0.98, SIR 5.11, 95% CI 1.65–11.95).Conclusions:There was a decreased cancer rate in PolyQ diseases despite high incidence of risk factors. Intriguingly, skin cancer incidence was higher, suggesting a crosstalk between neurodegeneration and skin tumorigenesis.
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Gkekas, Ioannis, Anna Gioran, Marina Kleopatra Boziki, Nikolaos Grigoriadis, Niki Chondrogianni, and Spyros Petrakis. "Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases." Antioxidants 10, no. 9 (September 13, 2021): 1450. http://dx.doi.org/10.3390/antiox10091450.
Повний текст джерелаАнотація:
Neurodegenerative polyglutamine (polyQ) disorders are caused by trinucleotide repeat expansions within the coding region of disease-causing genes. PolyQ-expanded proteins undergo conformational changes leading to the formation of protein inclusions which are associated with selective neuronal degeneration. Several lines of evidence indicate that these mutant proteins are associated with oxidative stress, proteasome impairment and microglia activation. These events may correlate with the induction of inflammation in the nervous system and disease progression. Here, we review the effect of polyQ-induced oxidative stress in cellular and animal models of polyQ diseases. Furthermore, we discuss the interplay between oxidative stress, neurodegeneration and neuroinflammation using as an example the well-known neuroinflammatory disease, Multiple Sclerosis. Finally, we review some of the pharmaceutical interventions which may delay the onset and progression of polyQ disorders by targeting disease-associated mechanisms.
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Xu, Jun, Jenny Chong, and Dong Wang. "Opposite roles of transcription elongation factors Spt4/5 and Elf1 in RNA polymerase II transcription through B-form versus non-B DNA structures." Nucleic Acids Research 49, no. 9 (April 20, 2021): 4944–53. http://dx.doi.org/10.1093/nar/gkab240.
Повний текст джерелаАнотація:
Abstract Transcription elongation can be affected by numerous types of obstacles, such as nucleosome, pausing sequences, DNA lesions and non-B-form DNA structures. Spt4/5 and Elf1 are conserved transcription elongation factors that promote RNA polymerase II (Pol II) bypass of nucleosome and pausing sequences. Importantly, genetic studies have shown that Spt4/5 plays essential roles in the transcription of expanded nucleotide repeat genes associated with inherited neurological diseases. Here, we investigate the function of Spt4/5 and Elf1 in the transcription elongation of CTG•CAG repeat using an in vitro reconstituted yeast transcription system. We found that Spt4/5 helps Pol II transcribe through the CTG•CAG tract duplex DNA, which is in good agreement with its canonical roles in stimulating transcription elongation. In sharp contrast, surprisingly, we revealed that Spt4/5 greatly inhibits Pol II transcriptional bypass of CTG and CAG slip-out structures. Furthermore, we demonstrated that transcription elongation factor Elf1 individually and cooperatively with Spt4/5 inhibits Pol II bypass of the slip-out structures. This study uncovers the important functional interplays between template DNA structures and the function of transcription elongation factors. This study also expands our understanding of the functions of Spt4/5 and Elf1 in transcriptional processing of trinucleotide repeat DNA.
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Zuo, Lingyan, Weiqian Li, Jifang Shi, Yingzhen Su, Hongyan Shuai, and Xin Yu. "SynB3 Conjugated QBP1 Passes Blood-Brain Barrier Models and Inhibits PolyQ Protein Aggregation." Protein & Peptide Letters 29, no. 1 (January 2022): 110–20. http://dx.doi.org/10.2174/0929866529666211221163930.
Повний текст джерелаАнотація:
Background: Polyglutamine diseases are degenerative diseases in the central nervous system caused by CAG trinucleotide repeat expansion which encodes polyglutamine tracts, leading to the misfolding of pathological proteins. Small peptides can be designed to prevent polyglutamine diseases by inhibiting the polyglutamine protein aggregation, for example, polyglutamine binding peptide 1(QBP1). However, the transportation capability of polyglutamine binding peptide 1 across the blood-brain barrier is less efficient. We hypothesized whether its therapeutic effect could be improved by increasing the rate of membrane penetration. Objectives: The objective of the study was to explore whether polyglutamine binding peptide 1 conjugated cell-penetrating peptides could pass through the blood-brain barrier and inhibit the aggregation of polyglutamine proteins. Methods: In order to investigate the toxic effects, we constructed a novel stable inducible PC12 cells to express Huntington protein that either has 11 glutamine repeats or 63 glutamine repeats to mimic wild type and polyglutamine expand Huntington protein, respectively. Both SynB3 and TAT conjugated polyglutamine binding peptide 1 was synthesized, respectively. We tested their capabilities to pass through a Trans-well system and subsequently studied the counteractive effects on polyglutamine protein aggregation. Results: The conjugation of cell-penetrating peptides to SynB3 and TAT enhanced the transportation of polyglutamine binding peptide 1 across the mono-cell layer and ameliorated polyglutamine-- expanded Huntington protein aggregation; moreover, SynB3 showed better delivery efficiency than TAT. Interestingly, it has been observed that polyglutamine binding peptide 1 specifically inhibited polyglutamine-expanded protein aggregation rather than affected other amyloidosis proteins, for example, β-Amyloid. Conclusion: Our study indicated that SynB3 could be an effective carrier for polyglutamine binding peptide 1 distribution through the blood-brain barrier model and ameliorate the formation of polyglutamine inclusions; thus SynB3 conjugated polyglutamine binding peptide 1 could be considered as a therapeutic candidate for polyglutamine diseases.
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Iyer, Shalini, K. Ravi Acharya, and Vasanta Subramanian. "A comparative bioinformatic analysis of C9orf72." PeerJ 6 (February 19, 2018): e4391. http://dx.doi.org/10.7717/peerj.4391.
Повний текст джерелаАнотація:
C9orf72 is associated with frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS), both of which are devastating neurodegenerative diseases. Findings suggest that an expanded hexanucleotide repeat in the non-coding region of the C9orf72 gene is the most common cause of familial FTD and ALS. Despite considerable efforts being made towards discerning the possible disease-causing mechanism/s of this repeat expansion mutation, the biological function of C9orf72 remains unclear. Here, we present the first comprehensive genomic study on C9orf72 gene. Analysis of the genomic level organization of C9orf72 across select species revealed architectural similarity of syntenic regions between human and mouse but a lack of conservation of the repeat-harboring intron 1 sequence. Information generated in this study provides a broad genomic perspective of C9orf72 which would form a basis for subsequent experimental approaches and facilitate future mechanistic and functional studies on this gene.
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Zhang, Shugang, Qixing Gong, Di Wu, Yun Tian, Lu Shen, Jie Lu, Ligang Xu, Hao Gu, Jianxia Xu, and Weiguo Liu. "Genetic and Pathological Characteristic Patterns of a Family With Neuronal Intranuclear Inclusion Disease." Journal of Neuropathology & Experimental Neurology 79, no. 12 (November 26, 2020): 1293–302. http://dx.doi.org/10.1093/jnen/nlaa142.
Повний текст джерелаАнотація:
Abstract Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder. This study aimed to investigate clinical, imaging, genetic, and dermatopathological characteristics of a family with adult-onset NIID. The proband was a 62-year-old woman with 3 brothers and 2 sisters. Of these, 4 had symptoms of paroxysmal visual field defect, extrapyramidal symptoms, dysautonomia, emotional changes, and cognitive dysfunction. Genetic examination revealed no abnormality related to cerebrovascular diseases. More than 200 CGG repeats of FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) whereas repeats of the proband were found 29 times, which excluded FXTAS. Quantitative reverse transcription polymerase chain reaction (PCR) and GC-rich-PCR identified an expanded GGC repeat (with ∼100 repeats) in the 5′ region of NOTCH2NLC in the patient and her 2 younger brothers. Pathological examination found eosinophilic intranuclear inclusions inside adipocytes, fibrocytes, and sweat gland cells. Immunohistochemistry and immunofluorescence staining revealed positive staining for ubiquitin and p62. The detailed pathological and genetic features of this NIID family provide a valuable contribution to the existing knowledge base of this rare disorder.
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Fischbeck, Kenneth H., Andrew Lieberman, Christine K. Bailey, Annette Abel, and Diane E. Merry. "Androgen receptor mutation in Kennedy'sdisease." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, no. 1386 (June 29, 1999): 1075–78. http://dx.doi.org/10.1098/rstb.1999.0461.
Повний текст джерелаАнотація:
Kennedy'sdisease is an X–linked form of motor neuron disease caused by an expanded polyglutamine repeat in the androgen receptor. While the expansion mutation causes some loss of transcriptional activity by the androgen receptor, the predominant effect of expansion is probably a toxic gain of function, similar to the mechanism of other polyglutamine expansion diseases. Features of the neurodegenerative phenotype of Kennedy'sdisease have now been reproduced in transgenic animals and neuronal cell culture. Nuclear inclusions of mutant androgen receptor protein are found in these model systems and in autopsy samples from patients with Kennedy'sdisease.
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HO, L. W., J. CARMICHAEL, J. SWARTZ, A. WYTTENBACH, J. RANKIN, and D. C. RUBINSZTEIN. "The molecular biology of Huntington's disease." Psychological Medicine 31, no. 1 (January 2001): 3–14. http://dx.doi.org/10.1017/s0033291799002871.
Повний текст джерелаАнотація:
Background. Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an increased CAG repeat number in a gene coding for a protein with unknown function, called huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract).Methods. This review describes the epidemiology, clinical symptomatology, neuropathological features and genetics of HD. The main aim is to examine important findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases caused by expanded polyglutamine tracts.Results. Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired energy metabolism, abnormal protein interactions and apoptosis.Conclusions. Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.