Department of Neurology, Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Lewy Body Dementia Association, Research Center of Excellence, Georgetown University Medical Center, Washington, DC 20057, USA.
Department of Chemistry, Georgetown University & Medicinal Chemistry Shared Resource, Georgetown University Medical Center, Washington, DC 20057, USA.
Int J Mol Sci. 2022 Jul 23;23(15):8131. doi: 10.3390/ijms23158131.
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.
泛素特异性蛋白酶 13（USP13）促进蛋白质去泛素化。帕金森病死后组织中 USP13 水平上调，而通过 shRNA 敲低 USP13 可降低动物模型中α-突触核蛋白水平。我们研究了表达慢病毒人α-突触核蛋白的 USP13 基因敲除小鼠中的 USP13 作用，并研究了 USP13 的小分子抑制剂 BK50118-C 对α-突触核蛋白病理和动物行为的影响。USP13 基因敲除小鼠单侧表达α-突触核蛋白，每日腹腔注射 100mg/kg BK50118-C 或 DMSO 连续 4 周，进行行为和功能测定。表达慢病毒人α-突触核蛋白的野生型 USP13 小鼠表现出运动和行为缺陷，但在部分（USP13）或完全（USP13）USP13 基因敲除小鼠中未观察到这些缺陷。BK50118-C 在体内显示出广泛且有利的治疗剂量范围。BK50118-C 治疗可显著减少野生型（USP13）而非 USP13 基因敲除小鼠中泛素化的α-突触核蛋白，增加多巴胺水平，并改善运动和行为症状。这些数据表明 USP13 对α-突触核蛋白的神经病理学至关重要，而新型 USP13 的小分子抑制剂可能是治疗α-突触核蛋白病的潜在药物。
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