{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T05:14:17Z","timestamp":1791954857584,"version":"4.3.4"},"reference-count":79,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":133,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01GM1905A"],"award-info":[{"award-number":["01GM1905A"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01GM1907A"],"award-info":[{"award-number":["01GM1907A"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>C-terminus of HSC70-interacting protein (CHIP) encoded by the gene STUB1 is a co-chaperone and E3 ligase that acts as a key regulator of cellular protein homeostasis. Mutations in STUB1 cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16) with widespread neurodegeneration manifesting as spastic-ataxic gait disorder, dementia and epilepsy. CHIP\u2212\/\u2212 mice display severe cerebellar atrophy, show high perinatal lethality and impaired heat stress tolerance. To decipher the pathomechanism underlying SCAR16, we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patients. We found impaired HSR induction and recovery compared to healthy controls. HSPA1A\/B transcript levels (coding for HSP70) were reduced upon heat shock but HSP70 remained higher upon recovery in patient- compared to control-fibroblasts. As SCAR16 primarily affects the central nervous system we next investigated the HSR in cortical neurons (CNs) derived from induced pluripotent stem cells of SCAR16 patients. We found CNs of patients and controls to be surprisingly resistant to heat stress with high basal levels of HSP70 compared to fibroblasts. Although heat stress resulted in strong transcript level increases of many HSPs, this did not translate into higher HSP70 protein levels upon heat shock, independent of STUB1 mutations. Furthermore, STUB1(\u2212\/\u2212) neurons generated by CRISPR\/Cas9-mediated genome editing from an isogenic healthy control line showed a similar HSR to patients. Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients. Our results question the role of impaired HSR in SCAR16 neuropathology and highlight the need for careful selection of proper cell types for modeling human diseases.<\/jats:p>","DOI":"10.1242\/dmm.045096","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T18:50:32Z","timestamp":1602528632000},"source":"Crossref","is-referenced-by-count":11,"title":["CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons"],"prefix":"10.1242","volume":"13","author":[{"given":"S.","family":"Schuster","sequence":"first","affiliation":[{"name":"University of T\u00fcbingen 1 Department of Neurology and Hertie Institute for Clinical Brain Research , , 72076 T\u00fcbingen , Germany"},{"name":"Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) 2 , 72076 T\u00fcbingen , Germany"},{"name":"Graduate School of Cellular and Molecular Neuroscience, University of T\u00fcbingen 3 , 72076 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Heuten","sequence":"additional","affiliation":[{"name":"University of T\u00fcbingen 1 Department of Neurology and Hertie Institute for Clinical Brain Research , , 72076 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Velic","sequence":"additional","affiliation":[{"name":"Proteome Center T\u00fcbingen, University of T\u00fcbingen, 72076 4 \u2008 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Admard","sequence":"additional","affiliation":[{"name":"Institute for Medical Genetics and Applied Genomics, University of T\u00fcbingen 5 , 72076 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Synofzik","sequence":"additional","affiliation":[{"name":"University of T\u00fcbingen 1 Department of Neurology and Hertie Institute for Clinical Brain Research , , 72076 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Ossowski","sequence":"additional","affiliation":[{"name":"Institute for Medical Genetics and Applied Genomics, University of T\u00fcbingen 5 , 72076 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Macek","sequence":"additional","affiliation":[{"name":"Proteome Center T\u00fcbingen, University of T\u00fcbingen, 72076 4 \u2008 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1022-7482","authenticated-orcid":false,"given":"S.","family":"Hauser","sequence":"additional","affiliation":[{"name":"University of T\u00fcbingen 1 Department of Neurology and Hertie Institute for Clinical Brain Research , , 72076 T\u00fcbingen , Germany"},{"name":"Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) 2 , 72076 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7774-5025","authenticated-orcid":false,"given":"L.","family":"Sch\u00f6ls","sequence":"additional","affiliation":[{"name":"University of T\u00fcbingen 1 Department of Neurology and Hertie Institute for Clinical Brain Research , , 72076 T\u00fcbingen , Germany"},{"name":"Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) 2 , 72076 T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,10,12]]},"reference":[{"key":"2024061302320672800_DMM045096C1","doi-asserted-by":"publisher","first-page":"2117","DOI":"10.1101\/gad.5.11.2117","article-title":"Attenuation of the heat shock response in HeLa cells is mediated by the release of bound heat shock transcription factor and is modulated by changes in growth and in heat shock temperatures","volume":"5","author":"Abravaya","year":"1991","journal-title":"Genes Dev."},{"key":"2024061302320672800_DMM045096C2","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1016\/j.biocel.2012.04.002","article-title":"Small heat shock proteins HSP27 (HspB1), alphaB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death","volume":"44","author":"Acunzo","year":"2012","journal-title":"Int. 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