13Running title: HtrA2/Omi to bestow a neuroprotective function Although the malfunction of HtrA2/Omi leads to Parkinson's disease (PD), the underlying 15 mechanism has remained unknown. Here, we showed that HtrA2/Omi specifically removed 16 oligomeric α-Syn but not monomeric α-Syn to protect oligomeric α-Syn-induced 17 neurodegeneration. Experiments using mnd2 mice indicated that HtrA2/Omi degraded oligomeric 18 α-Syn specifically without affecting monomers. Transgenic Drosophila melanogaster 19 experiments of the co-expression α-Syn and HtrA2/Omi and expression of genes individually also 20 confirmed that pan-neuronal expression of HtrA2/Omi completely rescued Parkinsonism in the α-21 Syn-induced PD Drosophila model by specifically removing oligomeric α-Syn. HtrA2/Omi 22 maintained the health and integrity of the brain and extended the life span of transgenic flies. 23 Because HtrA2/Omi specifically degraded oligomeric α-Syn, co-expression of HtrA2/Omi and α-24 Syn in Drosophila eye maintained a healthy retina, while the expression of α-Syn induced retinal 25degeneration. This work showed that the bacterial function of HtrA to degrade toxic misfolded 26 proteins is evolutionarily conserved in mammalian brains as HtrA2/Omi. 27 Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by 29 the progressive loss of dopaminergic neurons in the substantia nigra of the central nervous system 1 .
30The degeneration of the dopaminergic neurons of the substantia nigra results in clinical 31 manifestations such as motor impairments, which involve resting tremor, bradykinesia, postural 32 instability, gait difficulty and rigidity 2 . Although the degeneration of dopaminergic neurons 33 directly leads to the clinical manifestations of PD, the pathogenic mechanism underlying the 34 degeneration of dopaminergic neurons at the molecular level is still unclear. The most manifested 35 pathophysiological feature of dopaminergic neurons of PD is an abnormal accumulation of 36 oligomeric α-Synuclein (α-Syn) in the form of Lewy bodies and Lewy neuritis inside neurons, 37 which represent the major hallmarks of PD 3 . α-Syn is a 140-a.a. presynaptic protein that plays an 38 important role in maintaining a supply of synaptic vesicles in presynaptic terminals 4, 5 . α-Syn 39 performs its normal biological function in neurons if present as a monomer. However, the 40 monomeric form of α-Syn is naturally prone to adopt a β-sheet conformation to form oligomeric 41 aggregates 6 . The oligomeric α-Syn has very strong neurotoxicity such that the aggregation plays a 42 causative role in dopaminergic neuronal degeneration 7, 8 .
43Since the accumulation of misfolded α-Syn is key to the pathology of PD, the question of how 44 misfolded α-Syn is degraded by neurons has been actively investigated. Investigations over the 45 last decades have elucidated that the ubiquitin-proteasome system (UPS) and the autophagy-46 lysosomal pathway (ALP) work in conjunction to degrade α-Syn 9, 10 . However, neither UPS n...