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    Dysregulation of mRNA Transport and Translation in ALS

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    Author
    Coyne, Alyssa N.
    Issue Date
    2016
    Keywords
    Drosophila
    neurodegeneration
    ALS
    Advisor
    Zarnescu, Daniela C.
    
    Metadata
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release after 05-Dec-2017
    Abstract
    Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons. Although many cellular processes such as cytoskeletal maintenance and synaptic function are disrupted in ALS, the molecular mechanisms by which these defects arise remain poorly understood. TDP-43, an RNA binding protein linked to the majority of ALS cases, is involved in multiple aspects of RNA metabolism. It is hypothesized that TDP-43 may sequester its mRNA targets into cytoplasmic stress granules during disease progression in turn, inhibiting their localization and/or translation. This work uses a Drosophila model of ALS based on TDP-43, to provide evidence for TDP-43’s role in translation regulation of specific mRNA targets. Using a combination of genetic, molecular, and imaging approaches this work has identified TDP-43 induced post-transcriptional alterations in futsch and hsc70-4 mRNAs. First, futsch/MAP1B is a TDP-43 mRNA target altered at the level of mRNA localization and translation. This results in microtubule instability at the NMJ as evidenced by an increased number of satellite boutons and decreased number of Futsch positive loops that are thought to indicate stable synaptic contacts. Furthermore, overexpression of Futsch mitigates defects in microtubule stability and TDP-43 dependent locomotor dysfunction and also increases lifespan. Second, this work shows that synaptic expression of Hsc70-4, a molecular chaperone critical for synaptic vesicle cycling is involved in multiple steps of the synaptic vesicle cycle, is reduced at the NMJ when TDP-43 is overexpressed in motor neurons. Using a combination of electrophysiology and FM1-43 dye uptake assays, this work shows that motor neuron expression of TDP-43 induces defects in synaptic vesicle endocytosis. Third, this work identifies Fragile X Protein (FMRP) as a neuroprotective protein partner of TDP-43. FMRP overexpression remodels RNP granules, extracts TDP-43 from insoluble complexes, and restores the translation of specific TDP-43 targets. Together, these data provides evidence for translation dysregulation underlying microtubule instability and synaptic dysfunction in ALS pathogenesis and identifies restoration of translation via remodeling RNP granules as a neuroprotective strategy to mitigate toxicity.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Neuroscience
    Degree Grantor
    University of Arizona
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