Oligomeric α-Synuclein-Specific Degradation by HtrA2/Omi to Bestow a Neuroprotective Function

Abstract

Although the malfunction of HtrA2/Omi leads to Parkinson's disease (PD), the underlying mechanism has remained unknown. Here, we showed that HtrA2/Omi specifically removed oligomeric α-Syn but not monomeric α-Syn to protect oligomeric α-Syn-induced neurodegeneration. Experiments using nmd2 mice indicated that HtrA2/Omi degraded oligomeric α-Syn specifically without affecting monomers. Transgenic Drosophila melanogaster experiments of the co-expression α-Syn and HtrA2/Omi and expression of genes individually also confirmed that pan-neuronal expression of HtrA2/Omi completely rescued Parkinsonism in the α-Syn-induced PD Drosophila model by specifically removing oligomeric α-Syn. HtrA2/Omi maintained the health and integrity of the brain and extended the life span of transgenic flies. Because HtrA2/Omi specifically degraded oligomeric α-Syn, co-expression of HtrA2/Omi and α-Syn in Drosophila eye maintained a healthy retina, while the expression of α-Syn induced retinal degeneration. This work showed that the bacterial function of HtrA to degrade toxic misfolded proteins is evolutionarily conserved in mammalian brains as HtrA2/Omi. Funding: This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF2017M3C7A1044818) and also partially funded by JINIS BDRD Research Institute. Declaration of Interest: The authors declare no competing interests. Ethical Approval: The protocol was approved by the Ethics Committee of Chonbuk National University Laboratory Animal Center (Permit Number: CBU 2012-0040).