Identification of neuroprotective genes against alpha-synuclein toxicity using a Caenorhabditis elegans Parkinson disease model

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dc.contributor O'Donnell, Janis M.
dc.contributor Ramonell, Katrina M.
dc.contributor Zhang, Jianhua
dc.contributor.advisor Caldwell, Guy A.
dc.contributor.advisor Caldwell, Kim A. Hamamichi, Shusei 2017-02-28T22:21:43Z 2017-02-28T22:21:43Z 2009
dc.identifier.other u0015_0000001_0000128
dc.identifier.other Hamamichi_alatus_0004D_10197
dc.description Electronic Thesis or Dissertation
dc.description.abstract Recent functional analyses of nine gene products linked to familial forms of Parkinson disease (PD) have revealed several cellular mechanisms that are associated with PD pathogenesis. For example, alpha-synuclein (alpha-syn), a primary component of Lewy bodies found in both familial and idiopathic forms of PD, has been shown to cause defects in proteasomal and lysosomal protein degradation machineries and induce mitochondrial/oxidative stress. These findings are further supported by the fact that additional gene products are involved in the same pathways. While these studies have been invaluable to elucidate the etiology of this disease, it has been reported that monogenic forms of PD only account for 5-10% of all PD cases, indicating that multiple genetic susceptibility factors and intrinsic metabolic changes associated with aging may play a significant role. Here we report the use of an organism, Caenorhabditis elegans, to model two central PD pathological features to rapidly identify genetic components that modify alpha-syn misfolding in body wall muscles and neurodegeneration in DA neurons. We determined that proteins that function in lysosomal protein degradation, signal transduction, vesicle trafficking, and glycolysis, when knocked down by RNAi, enhanced alpha-syn misfolding. Furthermore, these components, when overexpressed, rescued DA neurons from alpha-syn-induced neurodegeneration, and several of them have been validated using mammalian system. Taken together, this study represents a novel set of gene products that are putative genetic susceptibility loci and potential therapeutic targets for PD.
dc.format.extent 207 p.
dc.format.medium electronic
dc.format.mimetype application/pdf
dc.language English
dc.language.iso en_US
dc.publisher University of Alabama Libraries
dc.relation.ispartof The University of Alabama Electronic Theses and Dissertations
dc.relation.hasversion born digital
dc.rights All rights reserved by the author unless otherwise indicated.
dc.subject.other Biology, Molecular
dc.subject.other Biology, Neuroscience
dc.subject.other Biology, Genetics
dc.title Identification of neuroprotective genes against alpha-synuclein toxicity using a Caenorhabditis elegans Parkinson disease model
dc.type thesis
dc.type text University of Alabama. Dept. of Biological Sciences Biological Sciences The University of Alabama doctoral Ph.D.

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