Gene-by-environment stressor interactions integrate at the mitochondria to determine severity of detrimental proteostatic and cellular health-related phenotypes in C. elegans models of Parkinson’s disease

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dc.contributor Caldwell, Guy A.
dc.contributor Marcus, Stevan
dc.contributor O'Donnell, Janis M.
dc.contributor Jenny, Matthew J.
dc.contributor Shorter, James
dc.contributor.advisor Caldwell, Kim A. Martinez, Bryan A. 2018-06-04T14:57:25Z 2018-06-04T14:57:25Z 2017
dc.identifier.other u0015_0000001_0002845
dc.identifier.other Martinez_alatus_0004D_13318
dc.description Electronic Thesis or Dissertation
dc.description.abstract Parkinson’s disease (PD) associates with selective degeneration of midbrain dopaminergic neurons culminating in irreversible motor dysfunction such as gait instability and tremors. Despite the localized nature of toxicity, increasing evidence points to dysfunction of mitochondria, a ubiquitous organelle, as a prime contributor to onset of PD. For instance, numerous genes controlling selective mitochondrial destruction through autophagy (mitophagy) are mutated in familial cases of PD such as PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. However, the vast majority of PD cases are idiopathic either as a result of genetic risk factors, accumulated environmental toxicity, or both. Because of this, it is unknown to what degree mitochondria are involved in contributing to idiopathic progression of disease. Taking advantage of the powerful genetics, we have utilized well-established and predictive models of neuron toxicity in Caenorhabditis elegans in order to determine the interplay between genetic and environmental stress. Based on this we have undertaken three major investigative efforts. Firstly, we wished to determine how the mitochondrial unfolded protein response (UPRMT), an environmentally-induced stress response system, may alter neurodegenerative and proteotoxic phenotypes associated with α-synuclein (αS) in C. elegans dopaminergic neurons and find that dysregulation of this stress response pathway leads to non-apoptotic neuronal cell death independent of mitophagy. Next, we find that a bacterial secondary metabolite from a ubiquitous soil bacteria Streptomyces venezuelae disrupts normal protein homeostasis associated with numerous aggregate protein disease-linked proteins and leads to neurotoxicity. This protein homeostasis disruption was linked to strong disruption of the ubiquitin proteasome system, glutathione homeostasis disruption, and mitophagy alterations in C. elegans, linking environmental exposure to a common pathological hallmark of neurodegenerative disease. Lastly, we have tested the influence of enteric bacterial secondary metabolites on stress responsiveness of C. elegans in established reporter strains for numerous cellular defense machineries and linked these observations to dopaminergic neurodegeneration health. Through these studies we demonstrate an integral and central role of the mitochondria on the neurodegenerative potential elicited by toxic environmental stimulus and the innate genetic regulation of stress response pathways towards these environmental stimuli.
dc.format.extent 223 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 Cellular biology
dc.subject.other Molecular biology
dc.title Gene-by-environment stressor interactions integrate at the mitochondria to determine severity of detrimental proteostatic and cellular health-related phenotypes in C. elegans models of Parkinson’s disease
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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