title: Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model.
abstract: Genetic and idiopathic forms of Parkinson's disease (PD) are characterized by loss of dopamine (DA) neurons and typically the formation of protein inclusions containing the alpha-synuclein (α-syn) protein. Environmental contributors to PD remain largely unresolved but toxins, such as paraquat or rotenone, represent well-studied enhancers of susceptibility. Previously, we reported that a bacterial metabolite produced by Streptomyces venezuelae caused age- and dose-dependent DA neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. We hypothesized that this metabolite from a common soil bacterium could enhance neurodegeneration in combination with PD susceptibility gene mutations or toxicants. Here, we report that exposure to the metabolite in C. elegans DA neurons expressing human α-syn or LRRK2 G2019S exacerbates neurodegeneration. Using the PD toxin models 6-hydroxydopamine and rotenone, we demonstrate that exposure to more than one environmental risk factor has an additive effect in eliciting DA neurodegeneration. Evidence suggests that PD-related toxicants cause mitochondrial dysfunction, thus we examined the impact of the metabolite on mitochondrial activity and oxidative stress. An ex vivo assay of C. elegans extracts revealed that this metabolite causes excessive production of reactive oxygen species. Likewise, enhanced expression of a superoxide dismutase reporter was observed in vivo. The anti-oxidant probucol fully rescued metabolite-induced DA neurodegeneration, as well. Interestingly, the stress-responsive FOXO transcription factor DAF-16 was activated following exposure to the metabolite. Through further mechanistic analysis, we discerned the mitochondrial defects associated with metabolite exposure included adenosine triphosphate impairment and upregulation of the mitochondrial unfolded protein response. Metabolite-induced toxicity in DA neurons was rescued by complex I activators. RNA interference (RNAi) knockdown of mitochondrial complex I subunits resulted in rescue of metabolite-induced toxicity in DA neurons. Taken together, our characterization of cellular responses to the S. venezuelae metabolite indicates that this putative environmental trigger of neurotoxicity may cause cell death, in part, through mitochondrial dysfunction and oxidative stress.
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ray
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Martinez
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Berkowitz
authors.affiliation: 1] Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA [2] Departments of Neurobiology and Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Caldwell
authors.affiliation: 1] Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA [2] Departments of Neurobiology and Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000382:microbiology*; D004195:Disease Models, Animal; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D013302:Streptomyces / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001685:Biological Factors