Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology.

Ciarán C Lynch,Charbel Moussa,Christian Wolf,Michaeline Hebron,Xiaoguang Liu,Kaluvu Balaraman

doi:10.3390/metabo11090622

Ciarán C Lynch, Charbel Moussa + Show 4 more

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https://doi.org/10.3390/metabo11090622

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Abstract

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.

Highlights

Ubiquitin Specific Protease (USP)-13, named ubiquitin carboxyl-terminal hydrolase 13 which belongs to the family of cysteine proteases [1,2,3], promotes cleavage of ubiquitin chains, resulting in protein de-ubiquitination [4]
To further elucidate the role of Ubiquitin Specific Protease-13 (USP13) in neurodegeneration, we developed a small library of specific small molecule inhibitors of USP13
We previously demonstrated that USP13 reduces the E3 ubiquitin ligase activity of parkin via de-ubiquitination [21], while USP13 knockdown increases parkin ubiquitination and activity [21]

Summary

Introduction

Ubiquitin Specific Protease (USP)-13, named ubiquitin carboxyl-terminal hydrolase 13 which belongs to the family of cysteine proteases [1,2,3], promotes cleavage of ubiquitin chains, resulting in protein de-ubiquitination [4]. Alzheimer’s disease (AD) is characterized by tau hyper-phosphorylation that forms inclusions called tangles, along with plaque deposits containing amyloid-β (Aβ) peptides [8,9]. These neurotoxic proteins (tau, Aβ and alpha-synuclein) may co-exist in AD, PD and DLB [10,11,12,13,14,15,16,17,18]. USP13 knockdown via shRNA regulates the E3 ubiquitin ligase activity of autosomal recessive PD-linked parkin and increases the ubiquitination of alpha-synuclein and hyper-phosphorylated tau (p-tau), leading to enhanced proteasome clearance [20,21]. There is an urgent need to develop USP13 inhibitors and investigate their pharmacology in neurodegeneration

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