{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:33:32Z","timestamp":1790674412798,"version":"4.1.0"},"reference-count":54,"publisher":"Society for Neuroscience","issue":"10","license":[{"start":{"date-parts":[[2010,9,10]],"date-time":"2010-09-10T00:00:00Z","timestamp":1284076800000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2010,3,10]]},"abstract":"<jats:p>The presence of intracellular ubiquitylated inclusions in neurodegenerative disorders and the role of the ubiquitin\/proteasome system (UPS) in degrading abnormal hazardous proteins have given rise to the hypothesis that UPS-impairment underlies neurodegenerative processes. However, this remains controversial for polyglutamine disorders such as Huntington disease (HD). Whereas studies in cellular models have provided evidence in favor of UPS-impairment attributable to expression of the N-terminal fragment of mutant huntingtin (N-mutHtt), similar studies on mouse models failed to do so. Furthermore, we have recently shown that the increase in polyubiquitin conjugates reported in the brain of N-mutHtt mice occurs in the absence of a general UPS-impairment. In the present study we aim to clarify the potential of N-mutHtt to impair UPS function<jats:italic>in vivo<\/jats:italic>as well as the mechanisms by which neurons may adapt after prolonged exposure to N-mutHtt in genetic models. By combining UPS reporter mice with an inducible mouse model of HD, we demonstrate for the first time polyglutamine-induced global UPS-impairment<jats:italic>in vivo<\/jats:italic>. UPS-impairment occurred transiently after acute N-mutHtt expression and restoration correlated with appearance of inclusion bodies (IBs). Consistently, UPS recovery did not take place when IB formation was prevented through administration of N-mutHtt aggregation-inhibitors in both cellular and animal models. Finally, no UPS-impairment was detected in old mice constitutively expressing N-mutHtt despite the age-associated decrease in brain proteasome activity. Therefore, our data reconcile previous contradictory reports by showing that N-mutHtt can indeed impair UPS function<jats:italic>in vivo<\/jats:italic>and that N-mutHtt aggregation leads to long lasting restoration of UPS function.<\/jats:p>","DOI":"10.1523\/jneurosci.5673-09.2010","type":"journal-article","created":{"date-parts":[[2010,3,10]],"date-time":"2010-03-10T19:19:37Z","timestamp":1268248777000},"page":"3675-3688","source":"Crossref","is-referenced-by-count":82,"title":["Acute Polyglutamine Expression in Inducible Mouse Model Unravels Ubiquitin\/Proteasome System Impairment and Permanent Recovery Attributable to Aggregate Formation"],"prefix":"10.1523","volume":"30","author":[{"given":"Zaira","family":"Ortega","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"D\u00edaz-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa J.","family":"Maynard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e9lix","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico P.","family":"Dantuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 J.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2010,3,10]]},"reference":[{"key":"2023041303425676000_30.10.3675.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.004101"},{"key":"2023041303425676000_30.10.3675.2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02998"},{"key":"2023041303425676000_30.10.3675.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.292.5521.1552"},{"key":"2023041303425676000_30.10.3675.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.12.021"},{"key":"2023041303425676000_30.10.3675.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature06022"},{"key":"2023041303425676000_30.10.3675.6","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi423"},{"key":"2023041303425676000_30.10.3675.7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005128"},{"key":"2023041303425676000_30.10.3675.8","doi-asserted-by":"publisher","DOI":"10.1038\/nm1067"},{"key":"2023041303425676000_30.10.3675.9","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi064"},{"key":"2023041303425676000_30.10.3675.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800467200"},{"key":"2023041303425676000_30.10.3675.11","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn319"},{"key":"2023041303425676000_30.10.3675.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00606-8"},{"key":"2023041303425676000_30.10.3675.13","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.bbadis.2009.01.012","article-title":"A critical evaluation of the ubiquitin-proteasome system in Parkinson's disease","volume":"1792","author":"Cook","year":"2009","journal-title":"Biochim Biophys Acta"},{"key":"2023041303425676000_30.10.3675.14","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2091-8-S1-S2"},{"key":"2023041303425676000_30.10.3675.15","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0076-6879(99)09045-X","article-title":"Detection of polyglutamine aggregation in mouse models","volume":"309","author":"Davies","year":"1999","journal-title":"Methods Enzymol"},{"key":"2023041303425676000_30.10.3675.16","doi-asserted-by":"crossref","first-page":"11653","DOI":"10.1523\/JNEUROSCI.23-37-11653.2003","article-title":"Neuronal induction of the immunoproteasome in Huntington's disease","volume":"23","author":"Diaz-Hernandez","year":"2003","journal-title":"J Neurosci"},{"key":"2023041303425676000_30.10.3675.17","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2365-04.2004"},{"key":"2023041303425676000_30.10.3675.18","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3183-05.2005"},{"key":"2023041303425676000_30.10.3675.19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.03968.x"},{"key":"2023041303425676000_30.10.3675.20","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1523\/JNEUROSCI.09-11-03955.1989","article-title":"Development of inhibitory synapses among striatal neurons in vitro","volume":"9","author":"Dubinsky","year":"1989","journal-title":"J Neurosci"},{"key":"2023041303425676000_30.10.3675.21","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1673408"},{"key":"2023041303425676000_30.10.3675.22","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00027.2001"},{"key":"2023041303425676000_30.10.3675.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182426599"},{"key":"2023041303425676000_30.10.3675.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2003.12.002"},{"key":"2023041303425676000_30.10.3675.25","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.425"},{"key":"2023041303425676000_30.10.3675.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.07.007"},{"key":"2023041303425676000_30.10.3675.27","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.1523\/JNEUROSCI.06-10-03044.1986","article-title":"Primary culture of identified neurons from the visual cortex of postnatal rats","volume":"6","author":"Huettner","year":"1986","journal-title":"J Neurosci"},{"key":"2023041303425676000_30.10.3675.28","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.10.1049"},{"key":"2023041303425676000_30.10.3675.29","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.143.7.1883"},{"key":"2023041303425676000_30.10.3675.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(00)00067-1"},{"key":"2023041303425676000_30.10.3675.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0047-6374(99)00101-3"},{"key":"2023041303425676000_30.10.3675.32","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00274-X"},{"key":"2023041303425676000_30.10.3675.33","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(00)01852-3"},{"key":"2023041303425676000_30.10.3675.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.04.001"},{"key":"2023041303425676000_30.10.3675.35","doi-asserted-by":"publisher","DOI":"10.1038\/nbt851"},{"key":"2023041303425676000_30.10.3675.36","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81369-0"},{"key":"2023041303425676000_30.10.3675.37","doi-asserted-by":"crossref","first-page":"8772","DOI":"10.1523\/JNEUROSCI.21-22-08772.2001","article-title":"Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington's disease","volume":"21","author":"Martin-Aparicio","year":"2001","journal-title":"J Neurosci"},{"key":"2023041303425676000_30.10.3675.38","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5293.1678"},{"key":"2023041303425676000_30.10.3675.39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906463106"},{"key":"2023041303425676000_30.10.3675.40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806269200"},{"key":"2023041303425676000_30.10.3675.41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022628699"},{"key":"2023041303425676000_30.10.3675.42","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.29.051605.113042"},{"key":"2023041303425676000_30.10.3675.43","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7222-8"},{"key":"2023041303425676000_30.10.3675.44","unstructured":"Paxinos G Franklin KBJ (2001) The mouse brain in stereotaxic coordinates (Academic, New York), Ed 2.."},{"key":"2023041303425676000_30.10.3675.45","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80405-5"},{"key":"2023041303425676000_30.10.3675.46","doi-asserted-by":"publisher","DOI":"10.1038\/nm1066"},{"key":"2023041303425676000_30.10.3675.47","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20207"},{"key":"2023041303425676000_30.10.3675.48","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn211"},{"key":"2023041303425676000_30.10.3675.49","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00177-5"},{"key":"2023041303425676000_30.10.3675.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.06.033"},{"key":"2023041303425676000_30.10.3675.51","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn419"},{"key":"2023041303425676000_30.10.3675.52","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200709080"},{"key":"2023041303425676000_30.10.3675.53","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80623-6"},{"key":"2023041303425676000_30.10.3675.54","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200306038"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.5673-09.2010","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T19:49:35Z","timestamp":1681415375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.5673-09.2010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3,10]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2010,3,10]]},"published-print":{"date-parts":[[2010,3,10]]}},"alternative-id":["10.1523\/JNEUROSCI.5673-09.2010"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.5673-09.2010","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,3,10]]}}}