{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:51:42Z","timestamp":1792788702198,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011518","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000}}],"reference-count":111,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX004044"],"award-info":[{"award-number":["I01BX004044"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG066729"],"award-info":[{"award-number":["R01AG066729"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["R35GM142728"],"award-info":[{"award-number":["R35GM142728"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in\n                    <jats:italic>TARDBP<\/jats:italic>\n                    , the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Using a\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that\n                    <jats:italic>hsp-90<\/jats:italic>\n                    mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including\n                    <jats:italic>hsp-70<\/jats:italic>\n                    and\n                    <jats:italic>hsp-16<\/jats:italic>\n                    .\n                    <jats:italic>1<\/jats:italic>\n                    , and we demonstrate that normal levels of\n                    <jats:italic>hsp-16<\/jats:italic>\n                    .\n                    <jats:italic>1<\/jats:italic>\n                    are required for\n                    <jats:italic>hsp-90<\/jats:italic>\n                    mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    . Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies\n                    <jats:italic>in vivo<\/jats:italic>\n                    using a whole animal model of ALS.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011518","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T13:40:34Z","timestamp":1735220434000},"page":"e1011518","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis"],"prefix":"10.1371","volume":"20","author":[{"given":"Laura","family":"Garcia-Toscano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6428-4880","authenticated-orcid":true,"given":"Heather N.","family":"Currey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Hincks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jade G.","family":"Stair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7342-4136","authenticated-orcid":true,"given":"Nicolas J.","family":"Lehrbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1250-3871","authenticated-orcid":true,"given":"Nicole F.","family":"Liachko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,26]]},"reference":[{"issue":"10","key":"pgen.1011518.ref001","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1111\/ene.14393","article-title":"Amyotrophic lateral sclerosis: a clinical review","volume":"27","author":"P Masrori","year":"2020","journal-title":"Eur J Neurol"},{"issue":"3","key":"pgen.1011518.ref002","doi-asserted-by":"crossref","first-page":"e669","DOI":"10.1212\/NXG.0000000000000669","article-title":"Progress in Amyotrophic Lateral Sclerosis Gene Discovery: Reflecting on Classic Approaches and Leveraging Emerging Technologies.","volume":"8","author":"SN Smukowski","year":"2022","journal-title":"Neurol Genet"},{"key":"pgen.1011518.ref003","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s42466-019-0039-8","article-title":"Molecular mechanisms of proteinopathies across neurodegenerative disease: a review","volume":"1","author":"AP Marsh","year":"2019","journal-title":"Neurol Res Pract"},{"key":"pgen.1011518.ref004","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fnmol.2019.00025","article-title":"Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.","volume":"12","author":"A Prasad","year":"2019","journal-title":"Front Mol Neurosci."},{"issue":"2","key":"pgen.1011518.ref005","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/emboj.2010.310","article-title":"TDP-43 regulates its mRNA levels through a negative feedback loop","volume":"30","author":"YM Ayala","year":"2011","journal-title":"EMBO J"},{"issue":"5","key":"pgen.1011518.ref006","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1097\/WCO.0000000000001098","article-title":"Neuropathology and neuroanatomy of TDP-43 amyotrophic lateral sclerosis.","volume":"35","author":"K Del Tredici","year":"2022","journal-title":"Curr Opin Neurol"},{"key":"pgen.1011518.ref007","first-page":"11","article-title":"Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43.","author":"D Heo","year":"2022","journal-title":"Elife"},{"issue":"3","key":"pgen.1011518.ref008","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1080\/14728222.2018.1439923","article-title":"TDP-43 post-translational modifications in health and disease.","volume":"22","author":"E. 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