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Article

Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology

1
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
2
Department of Chemistry, Georgetown University & Medicinal Chemistry Shared Resource, Georgetown University Medical Center, Washington, DC 20057, USA
*
Author to whom correspondence should be addressed.
Xiaoguang Liu and Kaluvu Balaraman are co-first authors and equally contributed to this manuscript.
Academic Editor: Peter Meikle
Metabolites 2021, 11(9), 622; https://doi.org/10.3390/metabo11090622
Received: 27 July 2021 / Revised: 3 September 2021 / Accepted: 11 September 2021 / Published: 15 September 2021
(This article belongs to the Special Issue Brain Metabolomics: New Perspective on Neurodegenerative Disorders)
Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer’s disease (AD) and Parkinson’s 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. View Full-Text
Keywords: neurodegeneration; USP13; USP13 inhibitors neurodegeneration; USP13; USP13 inhibitors
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MDPI and ACS Style

Liu, X.; Balaraman, K.; Lynch, C.C.; Hebron, M.; Wolf, C.; Moussa, C. Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology. Metabolites 2021, 11, 622. https://doi.org/10.3390/metabo11090622

AMA Style

Liu X, Balaraman K, Lynch CC, Hebron M, Wolf C, Moussa C. Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology. Metabolites. 2021; 11(9):622. https://doi.org/10.3390/metabo11090622

Chicago/Turabian Style

Liu, Xiaoguang, Kaluvu Balaraman, Ciarán C. Lynch, Michaeline Hebron, Christian Wolf, and Charbel Moussa. 2021. "Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology" Metabolites 11, no. 9: 622. https://doi.org/10.3390/metabo11090622

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