USP10 is a critical factor in α-synuclein aggregation, aggresome and Lewy body formations but not GCI

Parkinson's disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative diseases characterized by the presence of α-synuclein protein aggregates in the brain lesions, called Lewy bodies (LB) and oligodendroglial cytoplasmic inclusion (GCI), respectively. α-synuclein aggregates, called aggresomes, are induced in cultured cells expressing α-synuclein, treated with proteasome inhibitor (PI). Accumulating evidence suggests that LB is formed through an aggresome-related mechanism, since LB and aggresome have similar constituent proteins and morphology each other. In this study, we provide an evidence that ubiquitin-specific protease 10 (USP10) is a critical factor in α-synuclein aggregate, aggresome and LB formations but not GCI. The treatment of cultured cells with PI induced one large protein aggregate at the perinuclear regions, detected with aggresome marker proteins ubiquitin/p62/HDAC6, and these aggresomes were colocalized with USP10. USP10 knockdown revealed that USP10 is critical in aggresome formation. USP10 interacted with a ubiquitin receptor p62, and the interaction augmented USP10-induced aggresome formation. α-synuclein was localized at aggresome in α-synuclein-overexpressing cells. In PD patients, phosphorylated α-synuclein and USP10 were colocalized at LB. Unlike LB, USP10 showed no colocalization with GCI in oligodendroglia in MSA patients. These differences were partly explained by the distinct expression level of USP10: high USP10 expression in neuron and low USP10 expression in oligodendroglia. The present study suggests that USP10 is a critical factor in α-synuclein aggregation and LB formation through aggresome-related mechanism. Distinct USP10 expression in neuron and oligodendroglia might play a role in distinct synucleinopathy in PD and MSA.