{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:20:32Z","timestamp":1792110032591,"version":"4.4.0"},"reference-count":56,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000135","name":"NIH Blueprint for Neuroscience Research","doi-asserted-by":"publisher","award":["R01 GM107129"],"award-info":[{"award-number":["R01 GM107129"]}],"id":[{"id":"10.13039\/100000135","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Exp Neurosci"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid \u03b2 (A\u03b2) and tau in Alzheimer disease, \u03b1-synuclein (\u03b1-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell\u2019s protein degradation system for individual proteins\u2014the ubiquitin proteasome system (UPS)\u2014does not function sufficiently in many NDs. The proteasome itself has received significant focus for years due to its obvious failure to degrade misfolded proteins in ND, but no general mechanism has been uncovered. We have recently found that specific pathologically relevant oligomers can potently and directly inhibit the proteasome. What is most interesting is that the misfolded protein\u2019s primary amino acid sequence was irrelevant to its ability to inhibit. Instead, the culprit is the 3-dimensional shape of the misfolded oligomers. It turns out that many misfolded proteins in ND can take on this proteasome-impairing shape suggesting that there could be a common mechanism for UPS impairment in many NDs. The proteasome is already an important target for treating cancer, could it also be targeted to broadly treat ND?<\/jats:p>","DOI":"10.1177\/1179069518794675","type":"journal-article","created":{"date-parts":[[2018,8,20]],"date-time":"2018-08-20T02:39:13Z","timestamp":1534732753000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":29,"title":["Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases?"],"prefix":"10.1177","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1502-676X","authenticated-orcid":false,"given":"David M","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV, 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