Genetic analyses of lipid metabolism pathways involved in alpha-synuclein-induced neurodegeneration using a Caenorhabditis elegans model of Parkinson’s disease

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dc.contributor Caldwell, Kim A.
dc.contributor Marcus, Stevan
dc.contributor O'Donnell, Janis M.
dc.contributor Ramonell, Katrina M.
dc.contributor Witt, Stephan N.
dc.contributor.advisor Caldwell, Guy A.
dc.contributor.author Zhang, Siyuan
dc.date.accessioned 2018-06-04T14:58:23Z
dc.date.available 2018-06-04T14:58:23Z
dc.date.issued 2017
dc.identifier.other u0015_0000001_0002906
dc.identifier.other Zhang_alatus_0004D_13286
dc.identifier.uri http://ir.ua.edu/handle/123456789/3582
dc.description Electronic Thesis or Dissertation
dc.description.abstract Parkinson’s disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding of the human α-synuclein protein is a key pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging. Lifespan extension via the suppression of IGF-1/insulin-like signaling (IlS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection. The nceh-1 gene of Caenorhabditis elegans encodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IlS downstream protein that was identified in a screen as a modulator of α-synuclein accumulation. The mechanism whereby cholesterol metabolism functionally impacts neurodegeneration induced by α-synuclein is undefined. Here we report that NCEH-1 protects dopaminergic neurons from α-synuclein-dependent neurotoxicity in Caenorhabditis elegans via a mechanism that is independent of lifespan extension. We discovered that the presence of cholesterol, LDLR-mediated cholesterol endocytosis, and cholesterol efflux are all essential to NCEH-1-mediated neuroprotection. In protecting from α-synuclein neurotoxicity, NCEH-1 also stimulates cholesterol-derived neurosteroid formation and lowers cellular reactive oxygen species in mitochondria. This study augments our understanding of how cholesterol metabolism can modulate a neuroprotective mechanism that attenuates α-synuclein neurotoxicity. Phosphatidylserine decarboxylase is embedded in the inner mitochondrial membrane and synthesizes phosphatidylethanolamine (PE). Normal levels of PE can decline with age in the brain. Here we used worms to test the hypothesis that low levels of PE alter the homeostasis of α-syn. In Caenorhabditis elegans, RNAi depletion of phosphatidylserine decarboxylase (psd-1) in dopaminergic neurons expressing α-syn accelerates neurodegeneration, which supplemental ethanolamine (ETA) rescues. ETA fails to rescue this degeneration when the last enzyme in the CDP–ETA PE synthesis pathway is knocked down. This finding suggests that ETA exerts its protective effect by boosting PE through the Kennedy pathway. Furthermore, four more drugs targeting PE deficiency are identified to protect against α-synuclein-induced neurodegeneration. Collectively, these studies illuminate the significance of lipid metabolism in modifying the functional consequences of α-syn overabundance. In pointing toward regulation of neuronal cholesterol and phospholipid turnover as a potential disease-modifying factor, this research opens potentially new therapeutic avenues for attenuating dopaminergic neurodegeneration and PD.
dc.format.extent 162 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.ispartof The University of Alabama Libraries Digital Collections
dc.relation.hasversion born digital
dc.rights All rights reserved by the author unless otherwise indicated.
dc.subject.other Neurosciences
dc.subject.other Genetics
dc.subject.other Molecular biology
dc.title Genetic analyses of lipid metabolism pathways involved in alpha-synuclein-induced neurodegeneration using a Caenorhabditis elegans model of Parkinson’s disease
dc.type thesis
dc.type text
etdms.degree.department University of Alabama. Dept. of Biological Sciences
etdms.degree.discipline Biological Sciences
etdms.degree.grantor The University of Alabama
etdms.degree.level doctoral
etdms.degree.name Ph.D.


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