A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans

Simple item page
dc.contributor.authorMartinez, B. A.
dc.contributor.authorKim, H.
dc.contributor.authorRay, A.
dc.contributor.authorCaldwell, G. A.
dc.contributor.authorCaldwell, K. A.
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherUniversity of Alabama Birmingham
dc.date.accessioned2023-09-29T12:44:55Z
dc.date.available2023-09-29T12:44:55Z
dc.date.issued2015
dc.description.abstractGene-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.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationMartinez, B. A., Kim, H., Ray, A., Caldwell, G. A., & Caldwell, K. A. (2015). A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans. In Cell Death & Disease (Vol. 6, Issue 10, pp. e1908–e1908). Springer Science and Business Media LLC. https://doi.org/10.1038/cddis.2015.270
dc.identifier.doi10.1038/cddis.2015.270
dc.identifier.orcidhttps://orcid.org/0000-0003-1580-6122
dc.identifier.orcidhttps://orcid.org/0000-0002-8283-9090
dc.identifier.orcidhttps://orcid.org/0000-0002-0133-0306
dc.identifier.orcidhttps://orcid.org/0000-0003-1362-371X
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12348
dc.languageEnglish
dc.language.isoen_US
dc.publisherNature Portfolio
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCAENORHABDITIS-ELEGANS
dc.subjectPARKINSONS-DISEASE
dc.subjectOXIDATIVE STRESS
dc.subjectNEURODEGENERATIVE DISEASE
dc.subjectMITOCHONDRIAL DYSFUNCTION
dc.subjectDEGRADATION
dc.subjectRISK
dc.subjectAGGREGATION
dc.subjectTOXICITY
dc.subjectFISSION
dc.subjectCell Biology
dc.titleA bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegansen_US
dc.typeArticle
dc.typetext

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
10.1038cddis.2015.270.pdf
Size:
2.42 MB
Format:
Adobe Portable Document Format
Download

Collections

Research and Publications - Department of Biological Sciences