{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T01:09:29Z","timestamp":1777338569681,"version":"3.51.4"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Polyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ\u2010encoding CAG repeats in the disease\u2010causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We set out to identify common genetic variant(s) that may affect the AO of polyQ diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three hundred thirty\u2010seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of <jats:italic>PIAS1<\/jats:italic> because PIAS1 is an E3 SUMO (small ubiquitin\u2010like modifier) ligase for huntingtin (HTT), the protein linked to HD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Biochemical analyses revealed that the ability of PIAS1<jats:sup>S510G<\/jats:sup> to interact with mutant huntingtin (mHTT) was less than that of PIAS1<jats:sup>WT<\/jats:sup>, resulting in lower SUMOylation of mHTT and lower accumulation of insoluble mHTT. Genetic knock\u2010in of PIAS1<jats:sup>S510G<\/jats:sup> in a HD mouse model (R6\/2) ameliorated several HD\u2010like deficits (including shortened life spans, poor grip strength and motor coordination) and reduced neuronal accumulation of mHTT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggest that <jats:italic>PIAS1<\/jats:italic> is a genetic modifier of polyQ diseases. The naturally occurring variant, PIAS1<jats:sup>S510G<\/jats:sup>, is associated with late AO in polyQ disease patients and milder disease severity in HD mice. Our study highlights the possibility of targeting PIAS1 or pathways governing protein homeostasis as a disease\u2010modifying approach for treating patients with HD. \u00a9 2021 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28896","type":"journal-article","created":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T02:38:08Z","timestamp":1640313488000},"page":"767-777","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A <scp>PIAS1<\/scp> Protective Variant <scp>S510G<\/scp> Delays <scp>polyQ<\/scp> Disease Onset by Modifying Protein Homeostasis"],"prefix":"10.1002","volume":"37","author":[{"given":"Yan Hua","family":"Lee","sequence":"first","affiliation":[{"name":"Taiwan International Graduate Program in Molecular Medicine National Yang Ming Chiao Tung University and Academia Sinica  Taipei Taiwan"},{"name":"Institute of Biomedical Sciences, Academia Sinica  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