USP30 Inhibition as a Therapeutic Strategy in Parkinson's Disease

大量的证据表明线粒体稳态功能障碍是一个关键的病理生理

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.