USP30 Inhibition as a Therapeutic Strategy in Parkinson's Disease

大量证据表明线粒体动态平衡失调是一种重要的病理生理机制 帕金森病(PD)的发病机制。维持一组功能正常的线粒体库需要 选择性降解功能失调的线粒体的系统(“有丝分裂”)。常染色体隐性遗传性帕金森病 帕金氏缺乏症直接与吞丝分裂缺陷有关。线粒体功能障碍导致帕金 转移到线粒体膜外，在那里它与PINK1(另一个基因突变 导致AR PD)泛素化线粒体蛋白，从而诱导线粒体与 自噬小体，随后是自噬降解。因此，失去帕金会导致 线粒体因吞丝功能受损而功能失调。。在这种情况下，我们假设增强 吞噬丝裂将保护α-突触核蛋白(α-syn)毒性Α-syn导致线粒体复合体I功能障碍， 可能通过直接与线粒体膜上的TOM20结合从而干扰 线粒体蛋白进口。相反，功能失调的线粒体会产生更多的活性氧。 物种(ROS)，与帕金森病大脑氧化损伤标志物的增加一致。此外，ROS可以 增加α同步积累。然而，有丝分裂在清除功能障碍的线粒体中的作用 α-Syn所致线粒体损伤的机制尚不清楚。USP30是一种脱泛素酶(DUB) 系在线粒体膜外，在那里它直接移除由 帕金，从而抵消了帕金促进有丝分裂的能力。SiRNA救援击倒USP30基因 帕金缺陷细胞的有丝分裂和保护帕金缺陷果蝇的多巴胺能神经元。和 我们的初步数据表明，USP30基因敲除小鼠表现出增强的有丝分裂吞噬能力和对 α-SYN毒性。因此，抑制USP30是一种有吸引力的恢复吞噬丝裂原的治疗策略，以实现 帕金森病的神经保护。这些数据突出了帕金森病患者神经保护的主要潜力 通过靶向USP30调控有丝分裂吞噬。考虑到这一目标，我们现在建议测试一个高度 特异性中枢神经系统穿透性小分子抑制剂USP30对慢性退行性α综合征的神经保护作用 建立帕金森病小鼠模型，评估α清除和神经保护与帕金森病的关系 抑制USP30对介导α突触蛋白降解的特定途径的影响。这些结果可能会提供 支持使用MTX012或其他脑穿透药理USP30抑制剂 帕金森病的临床神经保护研究。

A large body of evidence implicates dysfunction of mitochondrial homeostasis as a key pathophysiological mechanism in Parkinson’s disease (PD). Maintenance of a pool of healthy functioning mitochondria requires a system for selectively degrading dysfunctional mitochondria (“mitophagy”). Autosomal recessive (AR) PD due to Parkin deficiency links directly to a defect in mitophagy. Mitochondrial dysfunction causes Parkin to translocate to the outer mitochondrial membrane where it interacts with PINK1 (another gene where mutations cause AR PD) to ubiquitinate mitochondrial proteins, thereby inducing fusion of mitochondria with autophagosomes, followed by autophagic degradation. Thus, loss of Parkin leads to the accumulation of dysfunctional mitochondria due to impaired mitophagy. . In this context, we hypothesize that enhancing mitophagy will protect against α-synuclein (αSyn) toxicity ΑSyn induces mitochondrial complex I dysfunction, potentially by directly binding to TOM20 on the mitochondrial membrane and thereby interfering with mitochondrial protein import. Conversely, dysfunctional mitochondria produce increased reactive oxygen species (ROS), consistent with increased markers of oxidative damage in the PD brain. Furthermore, ROS can increase αSyn accumulation. However, the role of mitophagy in clearing away dysfunctional mitochondria in the setting of αSyn induced mitochondrial impairment is unknown. USP30 is a deubiquitinating enzyme (DUB) tethered to the outer mitochondrial membrane, where it directly removes ubiquitin that had been attached by Parkin, thereby counteracting Parkin’s ability to promote mitophagy. Knock-down of USP30 by siRNA rescues mitophagy in Parkin-deficient cells and protects dopaminergic (DA) neurons in Parkin-deficient Drosophila. And our preliminary data suggest that USP30 knock-out mice show enchanced mitophagy and protection against αSyn toxicity. Thus, inhibition of USP30 is an attractive therapeutic strategy for restoring mitophagy to achieve neuroprotection in PD. These data highlight the major potential for neuroprotection in PD by specifically modulating mitophagy through targeting of USP30. With this goal in mind, we now propose to test a highly specific CNS-penetrant small molecular inhibitor of USP30 for neuroprotection in a slowly degenerative αSyn- based mouse model of PD, and to assess the degree to which αSyn clearance and neuroprotection relates to the impact of USP30 inhibition on specific pathways mediating αSyn degradation. These results could provide support for moving forward with MTX012 or other brain-penetrant pharmacological USP30 inhibitors towards clinical neuroprotection studies in PD.