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

Aggregation and misfolding of a-Synuclein (a -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 path-ophysiological functions between HtrA2 and a -Syn in the pathogenesis of PD remain unclear. This study shows that HtrA2 serine protease selectively recognizes and interacts with the NAC region of a -Syn. Interestingly, we found that HtrA2 causes proteolysis of a -Syn to prevent mitochondrial accumulation of a -Syn, thereby inhibiting the production of reactive oxygen species (ROS) in the mitochondria. We have further demonstrated that HtrA2 knockdown promotes a-Syn-mediated mitochondrial ROS production, thereby activating microglial cells. This study is the first to demonstrate that the HtrA2/a-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.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

Automated summary

This study demonstrates the selective interaction between HtrA2 protease and the NAC region of α-Synuclein, leading to the inhibition of mitochondrial accumulation of α-Synuclein and the production of reactive oxygen species. It further shows that the knockdown of HtrA2 promotes α-Synuclein-mediated mitochondrial ROS production and activation of microglial cells.