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 mnd2 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.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the central nervous system[1]
To confirm our speculation concerning whether the function of HtrA2/Omi in mammals is evolutionary conserved to protect neurons from oligomeric α-Syn-induced toxicity, we examined how human recombinant HtrA2/Omi produced in E. coli BL21 (DE3) pLysS-pET28a+ reacted with oligomerized α-Syn
HtrA2/Omi is a mitochondrial protein with high homology to a bacterial heat shock protein[15,16]
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the central nervous system[1]. Because the main function of HtrA/DegP in bacteria is to recognize misfolded or aggregated proteins to degrade those proteins, we speculated that HtrA2/Omi could play an important role in removing misfolded or aggregated proteins in mammals as it does in bacteria. Because all the in vivo and clinical data consistently indicate that HtrA2/Omi is linked to PD progression and oligomeric α-Syn is the main misfolded protein aggregate in neurons, we investigated the potential molecular mechanism of HtrA2/Omi in terms of whether it inhibits the formation of misfolded α-Syn or degrades oligomeric α-Syn to prevent PD. All of our in vitro and in vivo experiments using transgenic Drosophila and mice showed that HtrA2/Omi recognizes and degrades oligomeric α-Syn but not monomeric α-Syn, indicating that HtrA2/Omi prevents oligomeric α-Syn-induced neurotoxicity to protect neurons from neurodegeneration by removing misfolded or aggregated proteins, i.e., oligomeric α-Syn, just like it does in bacteria
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