{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:25:26Z","timestamp":1791685526445,"version":"4.3.4"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/metabo11090622","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T23:34:11Z","timestamp":1631662451000},"page":"622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology"],"prefix":"10.3390","volume":"11","author":[{"given":"Xiaoguang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology, Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Lewy Body Dementia Association, Research Center of Excellence, Georgetown University Medical Center, 4000 Reservoir Rd. NW, Building D, Room 203-C, Washington, DC 20007-2145, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2020-269X","authenticated-orcid":false,"given":"Kaluvu","family":"Balaraman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgetown University & Medicinal Chemistry Shared Resource, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6684-8413","authenticated-orcid":false,"given":"Ciar\u00e1n C.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgetown University & Medicinal Chemistry Shared Resource, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaeline","family":"Hebron","sequence":"additional","affiliation":[{"name":"Department of Neurology, Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Lewy Body Dementia Association, Research Center of Excellence, Georgetown University Medical Center, 4000 Reservoir Rd. NW, Building D, Room 203-C, Washington, DC 20007-2145, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4447-3753","authenticated-orcid":false,"given":"Christian","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgetown University & Medicinal Chemistry Shared Resource, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charbel","family":"Moussa","sequence":"additional","affiliation":[{"name":"Department of Neurology, Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Lewy Body Dementia Association, Research Center of Excellence, Georgetown University Medical Center, 4000 Reservoir Rd. NW, Building D, Room 203-C, Washington, DC 20007-2145, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1146\/annurev-biochem-061516-044916","article-title":"Mechanisms of Deubiquitinase Specificity and Regulation","volume":"86","author":"Mevissen","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.cell.2005.11.007","article-title":"A Genomic and Functional Inventory of Deubiquitinating Enzymes","volume":"123","author":"Nijman","year":"2005","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Jacomin, A.C., Taillebourg, E., and Fauvarque, M.O. (2018). Deubiquitinating Enzymes Related to Autophagy: New Therapeutic Opportunities?. 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