Using C. elegans to investigate neuroprotective and risk-associated genes in Alzheimer’s disease

Show simple item record

dc.contributor Caldwell, Kim A.
dc.contributor Jenny, Matthew J.
dc.contributor O'Donnell, Janis M.
dc.contributor Standaert, David G.
dc.contributor.advisor Caldwell, Guy A. Griffin, Edward Franklin 2019-02-12T14:31:42Z 2019-02-12T14:31:42Z 2018
dc.identifier.other u0015_0000001_0003229
dc.identifier.other Griffin_alatus_0004D_13666
dc.description Electronic Thesis or Dissertation
dc.description.abstract Intracellular accumulation of toxic protein aggregates is the hallmark of neurodegenerative diseases, including Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s. Despite the association of AD with amyloid plaques, composed of the amyloid-β (Aβ) peptide, further pursuit into the etiology led to the prevailing model that intracellular accumulation and aggregation is the causative force of Aβ and that the formation of extracellular plaques may be a byproduct of cellular stress response. Thus, understanding the framework of intracellular trafficking and communication in the context of proteotoxicity will provide a clearer understanding of disease progression, in addition to a foundation for identifying therapeutic targets. To do this, we utilized the organism Caenorhabditis elegans to examine the role of vesicular transport between AD and PD models of neurodegeneration. Using these models, we show that the same lysosomal trafficking mechanisms operate in opposing activities between AD and PD models. Previously, we found that overexpression of wild-type and truncated forms of the human vacuolar sorting protein sorting 41 (hVps41) protein reduced neurodegeneration induced by α-synuclein, the proteotoxic agent of PD. Here, we show that overexpression of hVps41 or a truncate containing only the CHCR and WD40 domains also reduced Aβ toxicity, but that Aβ-mediated neurodegeneration was affected by intersecting endo-lysosomal pathways. Additionally, the protective effect of hVps41 overexpression was mediated through alternative pathways. Though there is no genetic determinant of AD, variation in the Apolipoprotein E (ApoE) gene is associated with the highest risk of AD. To investigate the relationship between ApoE and Aβ, we generated a transgenic co-expression model that recapitulates the clinical susceptibility profile associated with ApoE. Expression of ApoEε2 reduces neurodegeneration through a protective mechanism shared with ER-derived calcium influx and ApoEε4 mediates mitochondrial interactions that can be exploited through enhancing mitochondrial unfolded protein response to attenuate Aβ. Furthermore, none of the alleles affect lifespan per se, but reduce the depression of lifespan by Aβ. These studies demonstrate the utility of C. elegans as a tool for examining how neurons respond to AD-related stress, with the potential to identify therapeutic targets and provide an animal model of drug discovery.
dc.format.extent 206 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 Biology
dc.title Using C. elegans to investigate neuroprotective and risk-associated genes in Alzheimer’s disease
dc.type thesis
dc.type text University of Alabama. Department of Biological Sciences Biological Sciences The University of Alabama doctoral Ph.D.

Files in this item

This item appears in the following Collection(s)

Show simple item record

Search DSpace


My Account