{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:39:42Z","timestamp":1793381982711,"version":"4.5.0"},"reference-count":64,"publisher":"American Society for Clinical Investigation","issue":"21","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R35GM130292"],"award-info":[{"award-number":["1R35GM130292"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,8]]},"abstract":"<jats:p>\n                    Recent studies have identified multiple genetic variants of SEL1L-HRD1 endoplasmic reticulum\u2013associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here, we showed that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell\u2013specific deletion of SEL1L (\n                    <jats:italic>\n                      Sel1L\n                      <jats:sup>Pcp2Cre<\/jats:sup>\n                    <\/jats:italic>\n                    ) exhibited motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy analysis revealed dilated ER and fragmented nuclei in Purkinje cells of adult\n                    <jats:italic>\n                      Sel1L\n                      <jats:sup>Pcp2Cre<\/jats:sup>\n                    <\/jats:italic>\n                    mice, indicative of altered ER homeostasis and cell death. Finally, loss of Purkinje cells was associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellums of\n                    <jats:italic>\n                      Sel1L\n                      <jats:sup>Pcp2Cre<\/jats:sup>\n                    <\/jats:italic>\n                    mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.174725","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T12:00:37Z","timestamp":1727784037000},"source":"Crossref","is-referenced-by-count":12,"title":["Purkinje cell\u2013specific deficiency in SEL1L-HRD1 endoplasmic reticulum\u2013associated degradation causes progressive cerebellar ataxia in mice"],"prefix":"10.1172","volume":"9","author":[{"given":"Mauricio","family":"Torres","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent","family":"Pederson","sequence":"additional","affiliation":[{"name":"Department of Molecular & Integrative Physiology, University of Michigan Medical 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