Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice

Abstract

Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson’s disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior. Alpha-synuclein was expressed unilaterally in substantia nigra (SN) of USP13 deficient mice that were treated with a daily intraperitoneal injection of 100 mg/kg BK50118-C or DMSO for four consecutive weeks, and behavioral and functional assays were performed. Wild-type USP13+/+ mice expressing lentiviral human alpha-synuclein showed motor and behavioral defects that were not seen in partially (USP13+/−) or completely (USP13−/−) deficient USP13 mice. BK50118-C displayed a wide and favorable therapeutic dose range in vivo. Treatment with BK50118-C significantly reduced ubiquitinated alpha-synuclein, increased dopamine levels, and improved motor and behavioral symptoms in wild-type (USP13+/+), but not USP13 deficient, mice. These data suggest that USP13 is critical to the neuropathology of alpha-synuclein, whereas a novel small molecule inhibitor of USP13 is a potential therapeutic agent of alpha-synucleinopathies.

Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease

“…First, USP13 favors the inhibited degradation of α-Syn through autophagy. Second, USP13 knockdown can increase Parkin ubiquitination and activity, thereby reducing the level of α-Syn; the excessive expression of USP13 increases the expression of α-Syn [ 68 , 69 ]. Similarly, USP8 deubiquitination of the K63 linkage on α-Syn favors the inhibited lysosomal degradation of α-Syn, resulting in the accumulation of α-Syn in LBs [ 67 ].…”

Role of USP13 in physiology and diseases

“…Furthermore, USP13 knockdown markedly reversed the motor performance of PD mice induced by lentiviral α-synuclein transfer, functioning as indirect evidence for the regulation of USP13 on α-synuclein. Also, pharmacological inhibition of USP13 could lower the level of α-synuclein and improve motor and behavior defects ( Liu et al, 2021 ; Liu et al, 2022 ). Previous studies also demonstrated Parkin ubiquitination could promote the autophagic clearance of α-synuclein ( Lonskaya et al, 2013 ; Madsen et al, 2021 ); however, the increased α-synuclein ubiquitination resulting from USP13 knockdown was independent of Parkin, though USP13 reduction also increased Parkin ubiquitination and proteasome activity ( Liu et al, 2019b ).…”