Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases

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dc.citation.firstpage17733en_US
dc.citation.journalTitleScientific Reportsen_US
dc.citation.volumeNumber11en_US
dc.contributor.authorTjahjono, Elissaen_US
dc.contributor.authorPei, Jingqien_US
dc.contributor.authorRevtovich, Alexey V.en_US
dc.contributor.authorLiu, Terri-Jeanne E.en_US
dc.contributor.authorSwadi, Alishaen_US
dc.contributor.authorHancu, Maria C.en_US
dc.contributor.authorTolar, Joe G.en_US
dc.contributor.authorKirienko, Natalia V.en_US
dc.date.accessioned2021-09-23T17:11:38Zen_US
dc.date.available2021-09-23T17:11:38Zen_US
dc.date.issued2021en_US
dc.description.abstractMacroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of PINK1 and Parkin, two key regulators of mitophagy, are amongst the most common causes of heritable parkinsonism. This has led to the hypothesis that pharmacological stimulation of mitophagy may be a feasible approach to combat neurodegeneration. Toward this end, we screened ~ 45,000 small molecules using a high-throughput, whole-organism, phenotypic screen that monitored accumulation of PINK-1 protein, a key event in mitophagic activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes, including delaying paralysis in a C. elegans β-amyloid aggregation model in a PINK-1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.en_US
dc.identifier.citationTjahjono, Elissa, Pei, Jingqi, Revtovich, Alexey V., et al.. "Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases." <i>Scientific Reports,</i> 11, (2021) Springer Nature: 17733. https://doi.org/10.1038/s41598-021-97148-z.en_US
dc.identifier.digitals41598-021-97148-zen_US
dc.identifier.doihttps://doi.org/10.1038/s41598-021-97148-zen_US
dc.identifier.urihttps://hdl.handle.net/1911/111407en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/.en_US
dc.titleMitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseasesen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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