Dissertations / Theses on the topic 'Amyotrophic lateral sclerosis – Research'
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Frakes, Ashley E. "The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417649954.
Full textLikhite, Shibi B. "Therapeutic suppression of mutant SOD1 by AAV9-mediated gene therapy approach in Amyotrophic Lateral Sclerosis." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417394084.
Full textRajagopalan, Venkateswaran. "Evaluation of Upper Motor Neuron Pathology in Amyotrophic Lateral Sclerosis by MRI: Towards Identifying Noninvasive Biomarkers of the Disease." Cleveland State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=csu1288020485.
Full textToro, Gabriela. "Gene Therapy for Amyotrophic Lateral Sclerosis: An AAV Mediated RNAi Approach for Autosomal Dominant C9ORF72 Associated ALS." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1020.
Full textDraper, Christiana S. I. "ALS-induced Excitability Changes in Individual Motorneurons and the Spinal Motorneuron Network in SOD1-G93A Mice at Symptom Onset." Wright State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=wright1621064515386592.
Full textCaroppo, Paola. "Study of the clinical and preclinical stages of genetic forms of frontotemporal lobar degeneration (FTLD) and research of biomarkers of progression of the disease." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066116.
Full textFrontotemporal lobar degeneration (FTLD) are rare neurodegenerative dementias. 30-50% of FTLD has a genetic cause, most are mutations in C9orf72 and in progranulin gene (GRN). The aim of the thesis was to expand the mutational and phenotypic spectrum of GRN mutations. We identified the first partial deletions of GRN gene in patients with low plasmatic progranulin (the plasmatic progranulin is low in case of mutation), but without mutation detected by sequencing. We contributed to expand the clinical spectrum of the disease by describing a posterior cortical atrophy phenotype and lesions of the cerebral white matter in GRN patients, evocative feature of this genetic form. Finally, we studied the presymptomatic stage of the disease, while the first clinical trials develop, for a longitudinal approach with MRI and FDG-PET. The cerebral metabolism is reduced in the left temporal lobe 20 years before clinical onset and, after 20 months, the metabolism is reduced in the frontal regions and the cortical thickness in the left temporal regions. The lateral temporal lobe could thus be the "epicenter" of the disease, and the lesional process could secondarily progress towards the frontal regions. I also contributed to define the phenotypes associated with rare gene mutations in FTLD/FTLD-ALS. TARDBP is associated with a wide phenotypic spectrum; TBK1 is characterized by semantic dementia or not fluent aphasia associated with involvement of the anterior horn. This important study highlights the role of these mutations in the clinical spectrum of FTLD
Flowers, Joanna Mary. "Molecular studies in amyotrophic lateral sclerosis." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397027.
Full textSchymick, Jennifer. "The genetics of amyotrophic lateral sclerosis." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:f68f15c2-2875-46ba-bf25-8324c1dead91.
Full textTjust, Anton. "Extraocular Muscles in Amyotrophic Lateral Sclerosis." Doctoral thesis, Umeå universitet, Anatomi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-129638.
Full textAmyotrofisk lateralskleros (ALS) är en obotlig neurodegenerativ sjukdom som främst påverkar kroppens viljestyrda motoriska nervceller. ALS leder till förlamning, muskelförtvining och slutligen döden genom andningssvikt, vanligen inom tre till fem år efter sjukdomsdebuten. Av okända anledningar så bibehålls ögonmusklernas funktion mycket bättre vid ALS i jämförelse med andra muskler och är hos merparten av patienter i stort sett opåverkade. Ögonmusklerna är mycket specialiserade muskler som skiljer sig från andra muskler i kroppen på flera sätt, bland annat genom deras unika nervförsörjning och genom de satellitceller – muskelspecifika stamceller, som finns i dem. En ökad förståelse för hur dessa faktorer inverkar på ögonmusklernas motståndskraft vid ALS skulle kunna ge värdefulla ledtrådar till hur man skulle kunna sakta ned sjukdomens fortskridande i andra muskler vid ALS. Ögonmuskler och extremitetsmuskler från avlidna ALS-patienter och åldersmatchade friska kontroller, tillsammans med transgena möss med den sjukdomsalstrande mutationen SOD1G93A, studerades genom immunfluorescens och efterföljande mikroskopering. Antikroppar mot molekylerna Pax7, NCAM, MyoD, myogenin, Ki-67, laminin och dystrofin användes för att identifiera satellitceller och deras dotterceller i ögonmuskler och extremitetsmuskler. Antikroppar mot neurofilament och synaptofysin användes för att identifiera nerver och neuromuskulära synapser hos transgena SOD1-möss. Antikroppar mot toniska (tonic) och ryckande (twitch) muskelmyosinkedjor användes för att bestämma proportionen av och storleken på dessa typer av muskelfibrer i ögonmuskler från avlidna ALS-patienter och friska kontroller. Mängden satellitceller varierade mellan de främre och de mer bakre delarna i friska, humana ögonmuskler och var dubbelt så många i den främre delen av muskeln jämfört med den mellersta och bakre delen av muskeln. Celler som uttryckte satellitcellsmarkören Pax7 hittades även i icke-traditionella satellitcellspositioner i ögonmusklerna. Mängden satellitceller i ögonmusklerna från ALS-patienter var samma som hos friska kontroller. I extremitetsmusklerna hos ALS-patienter varierade mängden satellitceller mellan låga nivåer (liknande de hos friska åldrade, inaktiva individer) till höga nivåer, särskilt i muskler där sjukdomen fortskridit under lång tid. Dessutom varierade mängden satellitceller mellan övre och nedre extremiteter. Hos symptomatiska SOD1G93A-möss hade ögonmusklerna en mycket välbevarad innervation jämfört med bakbensmusklerna, där många neuromuskulära synapser saknade kontakt mellan nerven och motorändplattan. Proportionen muskelfibrer med toniska muskelmyosinkedjor var lägre hos ALS-patienter jämfört med friska kontroller. Denna minskning var tydligare hos patienter där sjukdomssymtomen hade debuterat i tugg- och ansiktsmuskulaturen – så kallad bulbär ALS. Dessutom fanns det i den här gruppen, men ingen annan studerad grupp, en stark korrelation mellan nedgången i toniska fibrer och patientens ålder. Värt att notera är att minskningen av toniska muskelfibrer saknade korrelation med hur länge patienten hade varit sjuk i ALS. Den generellt välbevarade innervationen i ögonmusklerna hos SOD1G93A-möss kan spegla distinkta inneboende egenskaper hos ögonmusklerna som är av vikt för bevarandet av ögonrörligheten vid ALS. Gällande satellitceller så antyder våra data att satellitceller och deras regenerativa kapacitet spelar en försumbar roll vid ALS i allmänhet och vid ögonmusklernas bevarande i synnerhet. Slutligen, även om ögonmuskler generellt är välbevarade vid ALS så är toniska muskelfibrer märkbart påverkade och detta kan spegla skillnader mellan olika nervcellsgruppers känslighet vid ALS.
Valbuena, Gabriel. "Metabolomic studies of amyotrophic lateral sclerosis." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/49719.
Full textSeals, Ryan M. "Risk Factors for Amyotrophic Lateral Sclerosis." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23205175.
Full textFang, Fang. "Epidemiologic studies of amyotrophic lateral sclerosis." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-671-2/.
Full textJohnston, Pamela. "Echovirus aetiology in amyotrophic lateral sclerosis." Thesis, Glasgow Caledonian University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.688246.
Full textMcHenry, Kristen L. "Respiratory Compromise in Amyotrophic Lateral Sclerosis." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2539.
Full textJonsson, P. Andreas. "Superoxide dismutase 1 and amyotrophic lateral sclerosis." Doctoral thesis, Umeå : Medical Biosciences, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-611.
Full textEnayat, Zinat Ellaheh. "Superoxide dismutase mutations and amyotrophic lateral sclerosis." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400500.
Full textMather, Mary Srikanti. "Putative protein abnormalities in amyotrophic lateral sclerosis." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239078.
Full textSundara, Rajan Sandeep. "Role of peroxiredoxins in amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/3784/.
Full textPuigdomenech, Poch Maria. "Development of therapeutic strategies for amyotrophic lateral sclerosis." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670740.
Full textLa esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa devastadora, por la cual actualmente no existen ningún tratamiento. La ELA se caracteriza por la pérdida progresiva de motoneuronas (MN) superiores e inferiores y la consiguiente atrofia muscular. Hoy en día se desconocen los mecanismos moleculares específicos que promueven la muerte de estas MN, aunque se han relacionado con múltiples procesos que incluyen tanto las MN como las células subyacentes, tales como el estrés oxidativo, la inflamación o la agregación de proteínas como la superóxido dismutasa 1. En esta tesis nosotros proponemos dos estrategias terapéuticas para el ELA: incrementar la eficiencia del silenciamiento de la proteína mutada SOD1 mediante terapia génica y estudiar el rol del ácido lisofosfatídico (LPA) como mediador de la inflamación, en la fisiopatología del ELA. En el primer capítulo, con el objetivo de reducir los niveles de RNA de la proteína mutada SOD1, administramos oligonucleótidos antisentido (ASO) conjugados a ligandos específicos, por así incrementar su internalización a las células. Los resultados presentados revelan la eficiente internalización de esta terapia en neuronas y células gliales. Además, la conjugación del ASO con el ligando DCPP reduce de manera más eficiente que los ASO no conjugados, los niveles de RNA de SOD1 en los ratones SOD1G93A. Sin embargo, la administración del ASO conjugado con el ligando DCPP en los ratones SOD1G93A no presenta efectos terapéuticos. En el segundo capítulo, como la inflamación es un factor común en varias condiciones neurológicas y sabiendo que el receptor LPA2 contribuye en la fisiopatología de la lesión medular, nos preguntamos si el LPA podría contribuir en la fisiopatología del ELA. Por esto cruzamos ratones nulos por el receptor LPA2 con ratones transgénicos SOD1G93A. Nuestros resultados demuestran que la ausencia del receptor LPA2 retarda la progresión de la enfermedad y evita la atrofia muscular en ratones SOD1G93A. Colectivamente los resultados presentados en esta tesis aportan nueva información que podrían servir para desarrollar estrategias para el tratamiento de la ELA.
Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder with no effective treatment currently available. ALS is characterized by the progressive loss of both upper and lower motoneuron (MN) and the consequent muscle atrophy. Nowadays the specific molecular mechanism that underline the MN death is unknown, however has been related several dysfunction mechanisms in MNs and the surrounding cells, such: oxidative stress, inflammation or aggregation of aberrant proteins like superoxide dismutase 1 (SOD1). In this thesis we propose two therapeutic strategies for ALS: increase the silencing efficiency of the mutated SOD1, by means of gene therapy and study the role of the lysophosphatidic acid (LPA) in the pathophysiology of ALS. In the first chapter, with the aim to reduce the RNA levels of the SOD1 mutated, we administrated antisense oligonucleotide (ASO) conjugated to specific ligands to increase the internalization of the molecule. The results present here reveal the efficient internalization of the therapy in neurons and glia cells. Furthermore, the conjugated- ASO with the ligand DCPP reduce more efficiently than the unconjugated ASO, the SOD1 RNA levels in the SOD1G93A mice, an experimental model of ALS. However, the administration of the conjugated-ASO with the ligand DCPP in the SOD1G93A mice, does not present therapeutic effects. In the second chapter, since inflammation is a hallmark of most neurological conditions and LPA2 has been reported that contribute to the pathophysiology of spinal cord injury, we wonder if LPA could be involved in the pathophysiology of ALS. To assess whether activation of LPA2 contributes to ALS, we crossed LPA2 null with SOD1G93A mice. Our results reveal that the absence of LPA2 delays onset and progression of the disease and prevent the muscle atrophy in ALS mice. Collectively the results presented here provide more novel data that could underline new therapeutic strategies for ALS.
Zetterström, Per. "Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis." Doctoral thesis, Umeå universitet, Klinisk kemi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-43898.
Full textWootz, Hanna. "Amyotrophic Lateral Sclerosis – A Study in Transgenic Mice." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7342.
Full textEkegren, Titti. "Transmethylation, Polyamines and Apoptosis in Amyotrophic Lateral Sclerosis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3952.
Full textGros-Louis, François. "Genetics of familial and sporadic amyotrophic lateral sclerosis." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111859.
Full textAbalkhail, Halah Abdullah. "Characterisation of a new familial amyotrophic lateral sclerosis." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419231.
Full textVan, Der Hulst Egberdina Jozefa. "Heterogeneity of cognitive impairment in amyotrophic lateral sclerosis." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6388.
Full textLorente, Pons Alejandro. "Investigation of oligodendroglial pathology in amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/20854/.
Full textMcGoldrick, P. "Investigating new mouse models of amyotrophic lateral sclerosis." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1388178/.
Full textFigueiredo, Joana Maria Serra de Oliveira Duarte. "The role of microRNAs in amyotrophic lateral sclerosis." Master's thesis, Faculdade de Ciências e Tecnologia, 2011. http://hdl.handle.net/10362/7991.
Full textMicroRNAs (miRNAs) are emerging as a primary mediator of gene regulation in many different cell types. There is increasing evidence that specific subsets of miRNA play a prominent role in the nervous system, both in development and in specific neurodegenerative diseases. This study aims to elucidate the role of microRNA in selective motor neuron death that is the hallmark of amyotrophic Lateral sclerosis (ALS). Pre-symptomatic time-point was chosen since the levels of miRNAs are highly likely to be altered as a secondary consequence of cell injury and death in ALS. Laser capture microdissection (LCM) was used to study miRNA profiles in motor neurons of spinal cord tissue from SOD1G93A mice, the best characterized model of ALS. In preliminary work, using miRNA specific chips we have identified 2 miRNAs which are dramatically upregulated before disease onset. In this study, high RNA quality was achieved from laser captured cells, which consist in a major advance towards obtaining meaningful results of these miRNAs expression in downstream applications. Despite LCM technology has become increasingly sophisticated; rapidly obtaining enough amount of starting material for downstream applications is still extremely challenging. The combination of this optimized technique with microarrays, followed by RT-qPCR may provide insights into potential contribution of microRNAs to progression of neurodegeneration of motor neurons in ALS.
Jones, Ashley Richard. "The genetics and spread of Amyotrophic Lateral Sclerosis." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/the-genetics-and-spread-of-amyotrophic-lateral-sclerosis(70f7a2e4-087c-47ec-9a1d-3b69d3e7f2c5).html.
Full textMartínez, Muriana Anna. "Modulation of the inflammatory response in amyotrophic lateral sclerosis." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/664221.
Full textAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis and death to patients due to the degeneration of motor neurons in the spinal cord and the brain. At present, therapy is mainly symptomatic and fails to halt disease progression. A common feature of ALS, and other neurological disorders, is the occurrence of an inflammatory reaction consisting of activated glial cells (microglia and astrocytes) within the central nervous system, and leukocytes, mainly macrophages, in the peripheral nerves. The inflammatory response is a physiological process with very precise control and plays an essential role in the removal of cell debris and the activation of repair processes in infected or injured tissues. However, immune cells also secrete cytotoxic mediators that exert damage in healthy neighboring cells and even lead to cell death. This dual sword edge of immune cells likely depends on regulatory mediators that are present in the milieu. However, in ALS, as well as, in other neurological conditions inflammatory response is believed to trigger greater hazardous than protective actions. Based on these evidences, in the present thesis we aimed at assessing whether modulation of key aspects of inflammation could ameliorate the clinical course of ALS disease. In particular, we have focused our interest in three main targets: (i) the proinflammatory colony stimulating factor 1 receptor; (ii) the anti-inflammatory cytokine, interleukin-37; (iii) the immunoresolvent agent, Maresin-1. We provide novel data demonstrating that these approaches confer neuroprotection against the clinical course of ALS disease.
Rahmani, Kondori Nazanin. "Developing and testing therapies for Amyotrophic Lateral Sclerosis (ALS)." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/34340.
Full textWood-Allum, Clare Alison. "Impaired mitochondrial anti-oxidant defence in amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485078.
Full textLemoignan, Josée. "Decision-making for assisted ventilation in amyotrophic lateral sclerosis." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101862.
Full textKieran, Dairin Mary. "Preventing motoneuron degeneration in models of amyotrophic lateral sclerosis." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412710.
Full textRyan, Sarah. "Modelling C9orf72-linked frontotemporal dementia and amyotrophic lateral sclerosis." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/modelling-c9orf72linked-frontotemporal-dementia-and-amyotrophic-lateral-sclerosis(92740fce-3f4a-43cc-afed-b0f40f71ed03).html.
Full textKaneb, Hannah Marlene Jostock. "Preclinical testing of potential therapeutics for Amyotrophic Lateral Sclerosis." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9606.
Full textWesenberg, Judith [Verfasser]. "Temporal lobe pathology in amyotrophic lateral sclerosis / Judith Wesenberg." Magdeburg : Universitätsbibliothek, 2017. http://d-nb.info/1139048422/34.
Full textKelhetter, Kaitlyn Marie. "Velopharyngeal Function During Speech Production in Amyotrophic Lateral Sclerosis." Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/297626.
Full textBergemalm, Daniel. "Mutant superoxide dismutase-1-caused pathogenesis in amyotrophic lateral sclerosis." Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-31116.
Full textGallart, Palau Xavier Ramon. "Synaptic frailty and mitochondrial dysfunction in familial amyotrophic lateral sclerosis." Doctoral thesis, Universitat de Lleida, 2016. http://hdl.handle.net/10803/386410.
Full textLa Esclerosis Lateral Amiotrófica (ELA) es una enfermedad neurodegenerativa de la motoneurona. Todas las motoneuronas se ven afectadas desde la corteza motora primaria hasta la unión neuromuscular. En 1993 la descubierta de mutaciones en el gen SOD1 abrió nuevos límites experimentales con la creación de los primeros roedores transgénicos para esta enfermedad. Desde ese momento y hasta la actualidad, la mutación más estudiada en la ELA ha sido la mutación SOD1-G93A. Los modelos transgénicos de esta mutación han revelado mecanismos esenciales de la neurodegeneración en la ELA, incluyendo la excitotoxicidad, la disfunción proteica y la degeneración axosináptica entre otras. En este trabajo hemos explorado los cambios moleculares que tienen lugar en los terminales C, unos terminales altamente especializados de las α-motoneuronas, en un modelo murino de ELA con la mutación SOD1-G93A. Además, también hemos focalizado nuestra atención sobre la relación patológica que se establece en la ELA familiar (ELAF) entre la mutación SOD1-G93A y las mitocondrias. En relación a los terminales C durante la ELAF, hemos encontrado cambios asociados con la aparición de síntomas, como por ejemplo el incremento de la expresión del factor neurotrófico Neuregulina-1, localizado por primera vez en la cisterna subsináptica de los terminales C. La Neuregulina-1 en esas estructuras de retículo endoplasmático fue observada dentro de vesículas extracelulares (VEs), sugiriendo que el análisis de la Neuregulina-1 dentro de VEs en la ELA resulta especialmente prometedor como biomarcador potencial para esta enfermedad. Así, nosotros hemos desarrollado también un nuevo método para purificar VEs, dado que este es un paso esencial previo al estudio de las proteínas asociadas con estas estructuras. Nuestro método aplicado a la purificación de VEs de tejidos complejos fue capaz de facilitar la identificación de la Neuregulina en VEs provenientes de tejidos clínicos y fluidos biológicos. En relación a las implicaciones de la mitocondria en la ELA, hemos encontrado que la mutación SOD1-G93A estabiliza la proteína PINK1 en las mitocondrias activando el factor nuclear NFκB en neuronas. La interacción secuencial entre la SOD1 mutante y el NFκB crea una clara disfunción sobre la capacidad proteolítica del proteosoma, la cual a su vez promueve co-agregación de la SOD1 mutante y PINK1 en estas células. Estos resultados suman un sustancial conocimiento mecanístico sobre los roles de la mitocondria en eventos degenerativos clásicos de la ELA, como es la agregación de proteínas disfuncionales en motoneuronas. Siguiendo nuestro estudio de la afectación mitocondrial en la ELA, hemos creado y caracterizado un nuevo modelo de Drosophila que expresa la mutación humana SOD1-G93A en fibras musculares torácicas bajo el promotor 24B. Este modelo de Drosophila transgénica recapitula con éxito en fenotipo mitocondrial característico de la ELA presentando importantes ventajas para la elección de nuevos compuestos terapéuticos. En definitiva, los resultados generados en esta tesis proporcionan evidencia experimental, extensa comprensión molecular y insinúan nuevos horizontes terapéuticos acerca de los mecanismos moleculares y eventos neurodegenerativos asociados con la disfunción sináptica y la disfunción mitocondrial en la ELAF.
Amyotrophic Lateral Sclerosis (ALS) is an orphan age-associated neurodegenerative disease. All motoneurones in ALS are affected by degenerative flow from the primary motor cortex to the neuromuscular junction. In 1993, mutations of the gene SOD1 opened new research avenues allowing for the generation of familial ALS experimental models in rodents. Since then, the FALS mutation SOD1-G93A has been extensively studied worldwide in ALS to date. Transgenic models for this SOD1 mutation have revealed essential mechanisms of neurodegeneration including excitotoxicity, proteinopathy and axosynaptic degeneration among others. In this dissertation, we explored the molecular changes that occur in C-terminals, a very specialised synapse type from α-motoneurones of SOD1-G93A rodents. Also, we focused on the pathological relationship between the FALS mutant SOD1-G93A and mitochondria in motoneurones. With regard to C-terminals in FALS motoneurones, we found changes that were symptomatically associated with the up-regulated expression of the neurotrophic factor Neuregulin-1 located for the first time in the subsurface system of C-boutons juxtaposed to α-motoneurones. Furthermore, Neuregulin-1 in these endoplasmic reticulum structures was observed inside extracellular vesicles, suggesting that analysis of Neuregulin-1 from extracellular vesicles in ALS holds promise as a potential reliable biomarker for that neurodegenerative disease. We therefore have developed a new method for isolation of extracellular vesicles, as this remains as an essential step for the study of molecules associated with these structures. Our method applied to purify extracellular vesicles from complex biological tissues was able to facilitate the identification of Neuregulin-1 in extracellular vessicles from clinical tissues and biological fluids. Regarding implications of mitochondria in ALS, we have found that the FALS mutant hSOD1-G93A stabilises PINK1 in mitochondria and subsequently activates NFκB in neuronal cells. Sequential interaction between hSOD1 and NFκB impairs the proteosome proteolitic function promoting co-aggregation of SOD1 and PINK1 in these cells. These results add substantial mechanistic insight on the roles of mitochondria in classical ALS-associated neurodegenerative events, including aggregation of dysfuntional proteins in motoneurones. Following our study of mitochondria affectation in ALS, we have created and characterised a novel Drosophila model that expresses human SOD1-G93A in thoracic muscles under the genetic muscular promoter 24B. Flies expressing human SOD1-G93A in thoracic muscles successfully recapitulate FALS mitochondrial phenotype with several advantages in front of the current available rodent models for this FALS mutation. Taken together, the results generated in this thesis provide experimental evidence, further molecular comprehension and promise novel therapeutic approaches to the molecular mechanisms and neurodegenerative events associated with synaptic frailty and mitochondrial disfunction in FALS.
Xu, Guang. "Identification of Novel Genetic Variations for Amyotrophic Lateral Sclerosis (ALS)." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/958.
Full textWatts, Stephanie Anne. "Perceptual and Physiologic Analysis of Dystussia in Amyotrophic Lateral Sclerosis." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/7105.
Full textChen, Yiquan Medical Sciences Faculty of Medicine UNSW. "The involvement of the Kynurenine pathway in amyotrophic lateral sclerosis." Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/43774.
Full textPramatarova, Albéna. "Role of CuZn superoxide dismutase in familial amyotrophic lateral sclerosis." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36684.
Full textIt has been hypothesized that the pathology observed in FALS cases with SOD1 mutations is due to a gain of a new deleterious function of the mutant enzyme and not to a simple loss of dismutase activity. However the exact mechanism of SOD1 toxicity is still unknown and the specificity of the degenerating cell populations remains to be addressed. In this work, we investigated whether the damage seen in ALS with SOD1 mutations results from direct motor neuron toxicity. We have generated transgenic animals carrying a human SOD1 cDNA with the G37R mutation associated with FALS, driven by the neurofilament light chain promoter in order to specifically express the mutant protein in neuronal tissues. We show that transgenic animals express high levels of the human SOD1 protein in neuronal tissues, especially in the spinal cord where the motor neurons are concentrated, but develop no apparent motor deficit at up to 2 years of age. Our animal model suggests that neuron specific expression of mutant human SOD1 might not be sufficient for the development of the disease in mice, and hints towards the involvement of additional yet unidentified cell types/mechanisms.
Skinner, Thomas. "Molecular and neurological effects of fenretinide on Amyotrophic Lateral Sclerosis." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32585.
Full textLa Sclérose latérale amyotrophique (SLA) est la maladie affectant les neurones moteurs adultes la plus commune. Il n'existe qu'un seul traitement pharmacologique approuvé par la FDA ayant certains effets bénéfiques, soit le Riluzole. Il est par ailleurs documenté que des concentrations d'acides gras polyinsaturés (PUFA) peuvent affecter la progression d'un état neurodégénératif. Cependant, la plupart des interventions s'appuient sur des suppléments nutritifs et ont une efficacité à long terme plutôt limitée. Cette thèse décrit une série de traitements utilisant le fenretinide, un rétinoïde synthétique capable d'altérer la concentration de PUFA dans les membranes, dans un modèle de souris de SLA (souris SOD1(G93A)). Les traitements ont entrainé un retardement du déclenchement de la maladie avec une meilleure coordination motrice ainsi qu'une espérance de vie améliorée. Le fenretinide a également accrue les niveaux plasmatiques de l'acide docosahexaenoique tout en diminuant les niveaux d'arachidonate ainsi que les produits de peroxydation lipidiques tel que malonyldialdehye et nitrotyrosine. L'analyse immunohistochimique de la moelle épinière a révélé une réduction significative de l'inflammation déterminé par la quantité d'astrocytes et de microglies activés présentes. Ces résultats indiquent que le fenretinide représente un traitement prometteur contre la SLA.
Horwitz-Martin, Rachelle L. (Rachelle Laura). "Acoustic features of impaired articulation due to amyotrophic lateral sclerosis." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/113789.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (pages 213-227).
Progressive bulbar motor deterioration resulting from amyotrophic lateral sclerosis (ALS) leads to speech impairment. Despite the devastating consequences of speech impairment to life quality, few options are available to objectively assess speech motor involvement. The overarching goal of this research was to derive objective measures of speech acoustics that can be used to support clinical decision making. To achieve this goal, we obtained 121 speech samples from 33 patients with ALS who repeated the phrase "Buy Bobby a puppy" five times in succession. In total, 342 acoustic features were semi-automatically extracted from each speech recording. Pearson correlations were computed between each feature and three metrics of overall speech severity: sentence intelligibility, speaking rate, and communication efficiency. The findings were grounded within a physiologic framework where acoustic features were grouped into one of three domains that when combined, were hypothesized to broadly characterize articulatory performance: articulatory specification, articulatory coupling, and articulatory consistency. To obtain the most accurate prediction of ALS with the features we extracted, we compared two machine learning algorithms: linear regression and random forest. In shuffle-split cross-validation, the strongest mean Pearson correlations we obtained between actual and predicted intelligibility, speaking rate, and communication efficiency were 0.67, 0.74, and 0.77, respectively (SD=0.077, 0.050, and 0.059, respectively). Of the three domains, the specificity features were the most strongly associated with intelligibility impairments (mean r=0.68), and coupling was the most strongly associated with slower speaking rate (mean r=0.73). Specificity and coupling yielded similar performances in communication efficiency prediction. Other contributions of this thesis are that it is the first to implement a framework of dysarthric speech in terms of three domains: specification, coupling, and consistency; the first to validate automated formant tracking in dysarthric speech; and the first to perform an in-depth investigation into physiologically-inspired acoustic features that describe articulatory impairments of patients with ALS. Novel findings include the presence of abnormal formant coupling patterns, which may suggest greater tonguejaw coupling, in patients with more severe dysarthria due to ALS. Areas of future research involve further feature discovery, improved analysis methods, and a deeper understanding of relations to articulatory kinematics.
by Rachelle L. Horwitz-Martin.
Ph. D. in Biomedical Engineering
Townsend, Seth A. (Seth Alan). "Development of novel diagnostics and therapeutics for amyotrophic lateral sclerosis." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/45948.
Full textIncludes bibliographical references (p. 224-236).
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with diagnostics and treatments that are ineffective at stopping the progression. This thesis examines new ways of both diagnosing and treating ALS, including 1) a gadolinium tetanus toxin C fragment (Gd-TTC) biomarker for axonal retrograde transport, 2) TTC-conjugated biodegradable nanoparticles, and 3) poly(glycerol-co-sebacate) acrylate (PGSA) and 3D scaffolds for human embryonic stem cell (hESC) and neuronal encapsulation.A Gd-TTC conjugate was developed and characterized that was shown to be highly visible under MRI and preserved the functionality of the native TTC protein in vitro. Live animal MRI imaging and immuno fluorescent staining of the spinal cord showed that the conjugate was transported to the central nervous system (CNS) and localized in motor neurons. H&E staining and biodistribution studies showed that GdTTC was well tolerated and bio available. Quantification of MRI and staining images showed that Gd-TTC was retrograde transported and that that this rate decreased during the disease progression of ALS in a transgenic mouse model, suggesting that Gd-TTC could be used as a biomarker for neurodegenerative diseases.TTC-conjugated nanoparticles were developed by synthesizing PLGA-PEG-biotin and using biotin binding proteins (avidin, streptavidin, and neutravidin) to specifically conjugate TTC to the nanoparticle surface. TTC nanoparticles were shown to selectively target neurons and not other cell types in vitro.
(cont.) Subsequent in vivo experiments showed that nanoparticles were well tolerated and that TTC was co-localized with neurons unilaterally, suggesting that TTC-conjugated nanoparticles may be a useful drug delivery system. Porous PGSA scaffolds were prepared and characterized by porosity, swelling, mass loss, toxicity and mechanical properties, and subsequently used to encapsulated hESC and neuroblastoma cells in vitro. Neuroblastoma cells proliferated and formed matrix fibrils, and fluorescent staining of undifferentiated hESCs showed the presence of all three germ layers. In vivo experiments showed that porous PGSA scaffolds were well-tolerated and promoted vascular ingrowths.
by Seth A. Townsend.
Ph.D.
Edet-Amana, E. "Muscle pathology in a mouse model of amyotrophic lateral sclerosis." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1331880/.
Full textAlsomali, Khayria. "Investigating RNA editing in the pathogenesis of amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/9182/.
Full textKilani, Maya. "Cognition and emotion in normal aging and amyotrophic lateral sclerosis." Aix-Marseille 2, 2003. http://www.theses.fr/2003AIX20694.
Full textThe great variety of emotional experience can be explained as a function of emotion-cognition interactions. Given that some cognitive aspects decline with age, in parallel to finer degrees of emotional control, the relationship between age and emotionally induced feeling states was examined. Older subjects, compared with younger participants, showed less positive affects and more negative emotions. Since neuropathological conditions, such as in degenerative diseases, present a considerable impact on brain processes, an evaluation of cognitive function and emotional reactivity was undertaken in patients with ALS, compared to matched controls. The evolution of these parameters over a one year period was assessed. ALS patients were significantly more depressed than controls, and depression increased over the study period. While there was no observable change in memory and retrieval non-frontal cognitive functions, a performance deficit linked to frontal executive processing was detected suggesting a very mild defect in cognitive function. These deficits, unlike neuromuscular function and depression, did not aggravate over the period of the study. Emotional reactivity, in spite of some variability that can be best explained in terms of the heterogeneity of patients' profiles, did not differ significantly between ALS patients and controls. The study provides evidence for a mild defect in frontal cognitive processing in ALS patients, that evolves only slowly, if at all, with time. On the contrary, the profile of emotional processing in ALS seems to be affected to some extent