title: A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans.
abstract: Gene-by-environment interactions are thought to underlie the majority of idiopathic cases of neurodegenerative disease. Recently, we reported that an environmental metabolite extracted from Streptomyces venezuelae increases ROS and damages mitochondria, leading to eventual neurodegeneration of C. elegans dopaminergic neurons. Here we link those data to idiopathic disease models that predict loss of protein handling as a component of disorder progression. We demonstrate that the bacterial metabolite leads to proteostatic disruption in multiple protein-misfolding models and has the potential to synergistically enhance the toxicity of aggregate-prone proteins. Genetically, this metabolite is epistatically regulated by loss-of-function to pink-1, the C. elegans PARK6 homolog responsible for mitochondrial maintenance and autophagy in other animal systems. In addition, the metabolite works through a genetic pathway analogous to loss-of-function in the ubiquitin proteasome system (UPS), which we find is also epistatically regulated by loss of PINK-1 homeostasis. To determine remitting counter agents, we investigated several established antioxidants and found that glutathione (GSH) can significantly protect against metabolite-induced proteostasis disruption. In addition, GSH protects against the toxicity of MG132 and can compensate for the combined loss of both pink-1 and the E3 ligase pdr-1, a Parkin homolog. In assessing the impact of this metabolite on mitochondrial maintenance, we observe that it causes fragmentation of mitochondria that is attenuated by GSH and an initial surge in PINK-1-dependent autophagy. These studies mechanistically advance our understanding of a putative environmental contributor to neurodegeneration and factors influencing in vivo neurotoxicity.
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: H
authors.initials: H
authors.lastname: Kim
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.|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: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.|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; D001343:Autophagy; D001427:Bacterial Toxins / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000201:enzymology; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D008928:Mitochondria / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000382:microbiology; D009474:Neurons / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D057165:Proteostasis Deficiencies / Q000382:microbiology; D013302:Streptomyces / Q000737:chemistry / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D001427:Bacterial Toxins; D029742:Caenorhabditis elegans Proteins; D005978:Glutathione; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D051844:alpha-Synuclein; C000592695:pink-1 protein, C elegans; D000099202:PTEN-Induced Putative Kinase