HtrA2 regulates α-Synuclein-mediated mitochondrial reactive oxygen species production in the mitochondria of microglia.

Aggregation and misfolding of α-Synuclein (α-Syn), a causative agent for Parkinson's disease (PD), and oxidative stress are tightly implicated in the pathogenesis of PD. Although more than 20 genes including HtrA2 have been identified as causative genes for PD, the molecular mechanisms underlying the pathophysiological functions between HtrA2 and α-Syn in the pathogenesis of PD remain unclear. This study shows that HtrA2 serine protease selectively recognizes and interacts with the NAC region of α-Syn. Interestingly, we found that HtrA2 causes proteolysis of α-Syn to prevent mitochondrial accumulation of α-Syn, thereby inhibiting the production of reactive oxygen species (ROS) in the mitochondria. We have further demonstrated that HtrA2 knockdown promotes α-Syn-mediated mitochondrial ROS production, thereby activating microglial cells. This study is the first to demonstrate that the HtrA2/α-Syn cellular partner may play a crucial role in the pathogenesis of PD and provide new insights into the pathological processes and effective therapeutic strategies for PD. [Display omitted] • HtrA2 selectively interacts with the hydrophobic NAC site of α-Syn. • HtrA2 prevents mitochondrial accumulation of α-Syn by proteolysis of α-Syn. • α-Syn–induced ROS in mitochondria was reduced by HtrA2. • Inactivation of HtrA2 caused α-Syn accumulation in microglia. • Inactivation of HtrA2 leads to an increase in mitochondrial ROS in the microglia. [ABSTRACT FROM AUTHOR]