{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:14:26Z","timestamp":1784546066994,"version":"3.55.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T00:00:00Z","timestamp":1681430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004605","name":"Zhengzhou University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004605","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    Spinocerebellar ataxia type 3 (SCA3), also known as Machado\u2013Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in the\n                    <jats:italic>ATXN3<\/jats:italic>\n                    gene that encodes an expanded tract of polyglutamine in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murine\n                    <jats:italic>Atxn3<\/jats:italic>\n                    or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed in the cerebellum and brainstem of 7- and 47-week-old\n                    <jats:italic>Atxn3<\/jats:italic>\n                    knockout and SCA3 transgenic mice, and also in relevant mouse and human cell lines. In older mice, we observed that wild-type ATXN3 impacts the cerebellar levels of K48-Ub proteins. In contrast, pathogenic ATXN3 leads to decreased brainstem abundance of K48-Ub species in younger mice and changes in both cerebellar and brainstem K63-Ub levels in an age-dependent manner: younger SCA3 mice have higher levels of K63-Ub while older mice have lower levels of K63-Ub compared to controls. Human SCA3 neuronal progenitor cells also show a relative increase in K63-Ub proteins upon autophagy inhibition. We conclude that wild-type and mutant ATXN3 differentially impact K48-Ub- and K63-Ub-modified proteins in the brain in a region- and age-dependent manner.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2023.1154203","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T01:05:21Z","timestamp":1681434321000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Regional and age-dependent changes in ubiquitination in cellular and mouse models of spinocerebellar ataxia type 3"],"prefix":"10.3389","volume":"16","author":[{"given":"Haiyang","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sokol V.","family":"Todi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry L.","family":"Paulson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria do Carmo","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nature22078","article-title":"Polyglutamine tracts regulate beclin 1-dependent autophagy","volume":"545","author":"Ashkenazi","year":"2017","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"3690","DOI":"10.1007\/s12035-018-1331-2","article-title":"Citalopram reduces aggregation of ATXN3 in a YAC transgenic mouse model of Machado-Joseph disease","volume":"56","author":"Ashraf","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"104697","DOI":"10.1016\/j.nbd.2019.104697","article-title":"Druggable genome screen identifies new regulators of the abundance and toxicity of ATXN3, the spinocerebellar ataxia type 3 disease protein","volume":"137","author":"Ashraf","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/nature06022","article-title":"Global changes to the ubiquitin system in Huntington's disease","volume":"448","author":"Bennett","year":"2007","journal-title":"Nature"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1111\/cei.13410","article-title":"Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients","volume":"200","author":"Bhatt","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"582361","DOI":"10.3389\/fcell.2020.582361","article-title":"Unanchored ubiquitin chains, revisited","volume":"8","author":"Blount","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3889","DOI":"10.1111\/febs.13906","article-title":"Atg1-independent induction of autophagy by theDrosophilaUlk3 homolog, ADUK","volume":"283","author":"Braden","year":"2016","journal-title":"FEBS J."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"3195","DOI":"10.1093\/hmg\/ddg344","article-title":"The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity","volume":"12","author":"Burnett","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1093\/hmg\/11.9.1075","article-title":"YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit","volume":"11","author":"Cemal","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3605","DOI":"10.1074\/jbc.M310939200","article-title":"Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways","volume":"279","author":"Chai","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1093\/hmg\/8.4.673","article-title":"Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3\/MJD and suppression of polyglutamine aggregation in vitro","volume":"8","author":"Chai","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"44889","DOI":"10.1074\/jbc.M106575200","article-title":"The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease","volume":"276","author":"Chai","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"eabc0418","DOI":"10.1126\/sciadv.abc0418","article-title":"Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases","volume":"6","author":"Chatrin","year":"2020","journal-title":"Sci. Adv."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s12929-019-0569-y","article-title":"Ubiquitin-mediated regulation of autophagy","volume":"26","author":"Chen","year":"2019","journal-title":"J. Biomed. 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Genet."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e109700","DOI":"10.15252\/embj.2021109700","article-title":"HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation","volume":"41","author":"Kelsall","year":"2022","journal-title":"EMBO J."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"13293","DOI":"10.1073\/pnas.1905873116","article-title":"The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells","volume":"116","author":"Kelsall","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1159\/000090035","article-title":"Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in Portugal","volume":"60","author":"Lima","year":"2005","journal-title":"Hum. 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A."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/S0014-5793(03)00748-8","article-title":"Domain architecture of the polyglutamine protein ataxin-3: a globular domain followed by a flexible tail","volume":"549","author":"Masino","year":"2003","journal-title":"FEBS Lett."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/jnc.14541","article-title":"Machado-Joseph disease\/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy","volume":"148","author":"Matos","year":"2019","journal-title":"J. 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A."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e12430","DOI":"10.1371\/journal.pone.0012430","article-title":"Understanding the role of the Josephin domain in the PolyUb binding and cleavage properties of ataxin-3","volume":"5","author":"Nicastro","year":"2010","journal-title":"PLoS One"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"E1401","DOI":"10.1073\/pnas.1716673115","article-title":"K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains","volume":"115","author":"Ohtake","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/s41586-021-03566-4","article-title":"Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection","volume":"594","author":"Otten","year":"2021","journal-title":"Nature"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41586-018-0026-1","article-title":"Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity","volume":"556","author":"Pao","year":"2018","journal-title":"Nature"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1055\/s-2007-971172","article-title":"Dominantly inherited ataxias: lessons learned from Machado-Joseph disease\/spinocerebellar ataxia type 3","volume":"27","author":"Paulson","year":"2007","journal-title":"Semin. 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Genet."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.molcel.2011.05.036","article-title":"Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP","volume":"43","author":"Scaglione","year":"2011","journal-title":"Mol. Cell"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.bbamcr.2013.08.012","article-title":"Regulation of proteasome activity in health and disease","volume":"1843","author":"Schmidt","year":"2014","journal-title":"Biochim. Biophys. 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Cell"}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1154203\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T01:05:24Z","timestamp":1681434324000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1154203\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,14]]},"references-count":56,"alternative-id":["10.3389\/fnmol.2023.1154203"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2023.1154203","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.02.01.526671","asserted-by":"object"}]},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,14]]},"article-number":"1154203"}}