The role of plastin in motor neuron diseases and identifying genetic modifiers of spinal muscular atrophy

Walsh, Melissa Brietta

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Year:: 2015
Contributor:: Walsh, Melissa Brietta (creator); Hart, Anne (Director); Sahin, Mustafa (Reader); Reenan, Robert (Reader); Mowry, Kimberly (Reader); Morrow, Eric (Reader); Brown University. BIOMED: Molecular Biology, Cell Biology, and Biochemistry (sponsor)
Genre:: theses
Subject:: C. elegans; plastin; ALS; SMA; motor neuron disease; Caenorhabditis elegans; Spinal muscular atrophy; Motor neurons--Diseases
Extent:: 13, 181 p.
DOI: https://doi.org/10.7301/Z0GB22F8

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Abstract:: Abstract of The role of plastin in motor neuron disease and identifying genetic modifiers of spinal muscular atrophy, by Melissa B. Walsh, Ph. D., Brown University, May 2015. Neurodegenerative diseases are becoming increasingly prevalent. This growth in incidence correlates with a high demand for treatment, which is not readily available for most of these diseases. Identification of common genetic modifiers that affect multiple diseases would enable a better understanding of the mechanism of pathogenesis of these diseases and provide possible therapeutic targets. Using the model system Caenorhabditis elegans (C. elegans) we assessed whether plastin, a previously identified genetic modifier in patients of Spinal Muscular Atrophy (SMA), was able to ameliorate the behavioral defects found in nematode models of SMA, Amyotrophic Lateral Sclerosis (ALS) and polyglutamine toxicity disease. Further genetic and biochemical screening was done in order to understand how plastin acts to ameliorate SMA defects. This study showed that plastin, an actin bundling protein is able to suppress various behavioral defects across the three disease models tested. It also identified the ortholog to heterogeneous nuclear ribonucleoprotein F and H (hnRNP F and hnRNP H) as a genetic modifier in C. elegans models of SMA and ALS. Analysis using a vertebrate neuronal system showed that SMN co-immunoprecipitates with PLS3, hnRNP F and hnRNP H. Staining in mouse primary motor neurons also shows a co-localization of SMN with PLS3, hnRNP F and hnRNP H in motor neuron processes. The genetic data in C. elegans combined with the vertebrate protein data suggest that SMN, PLS3 and hnRNP F/H could act in a complex together in motor neuron processes that is pertinent to SMA pathogenesis. Taken together, the identification of plastin and hnRNP F/H as cross disease modifiers suggests that they could be targeting a common mechanism perturbed in both diseases. Further validation in vertebrate disease models is required and if true would provide a novel therapeutic target for these diseases.
Notes:: Thesis (Ph.D. -- Brown University (2015)

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Walsh, Melissa Brietta, "The role of plastin in motor neuron diseases and identifying genetic modifiers of spinal muscular atrophy" (2015). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0GB22F8

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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations

Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department.
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