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    Functional Characterization of Novel PFN1 Mutations Causative for Familial Amyotrophic Lateral Sclerosis: A Dissertation

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    Authors
    Wu, Chi-Hong
    Faculty Advisor
    John E. Landers, PhD
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Neurology
    Document Type
    Doctoral Dissertation
    Publication Date
    2015-12-17
    Keywords
    Dissertations, UMMS
    Amyotrophic Lateral Sclerosis
    Drosophila
    Motor Neurons
    Profilins
    Mutation
    Amyotrophic Lateral Sclerosis
    Drosophila
    Motor Neurons
    Profilins
    PFN1 Mutations
    Genetics and Genomics
    Molecular and Cellular Neuroscience
    Nervous System Diseases
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    Abstract
    Amyotrophic lateral sclerosis (ALS) is a progressive adult neurodegenerative disease that causes death of both upper and lower motor neurons. Approximately 90 percent of ALS cases are sporadic (SALS), and 10 percent are inherited (FALS). Mutations in the PFN1 gene have been identified as causative for one percent of FALS. PFN1 is a small actin-binding protein that promotes actin polymerization, but how ALS-linked PFN1 mutations affect its cognate functions or acquire gain-of-function toxicity remains largely unknown. To elucidate the contribution of ALS-linked PFN1 mutations to neurodegeneration, we have characterized these mutants in both mammalian cultured cells and Drosophila models. In mammalian neuronal cells, we demonstrate that ALS-linked PFN1 mutants form ubiquitinated aggregates and alter neuronal morphology. We also show that ALS-linked PFN1 mutants have partial loss-of-function effects on actin polymerization in growth cones of mouse primary motor neurons and larval neuromuscular junctions (NMJ) in Drosophila. In Drosophila, we also observe that PFN1 level influences integrity of adult motor neurons, as demonstrated by locomotion, lifespan, and leg NMJ morphology. In sum, the work presented in this dissertation has shed light on PFN1- linked ALS pathogenesis by demonstrating a loss-of-function mechanism. We have also developed a Drosophila PFN1 model that will serve as a valuable tool to further uncover PFN1-associated cellular pathways that mediate motor neuron functions.
    DOI
    10.13028/M2WS38
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32185
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2WS38
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