Omi/HtrA2 Is A Novel Regulator Of Autophagy That Participates The Pathogenesis Of Neurodegenerative Diseases

Neurodegenerative disease cause behavior disorders that caused by the irreversible deterioration of certain neurons in patients' brains. These diseases includes:Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Machado-Joseph disease (MJD). Alone with environmental factors, it was reported that the mutation of certain genes would also lead to neurodegenerative disease. For instance, the mutation of gene coding for alpha-synuclein protein is associated with early onset Parkinson's disease. The mutated alpha-synuclein protein is prone to form protein aggregates, which is the hallmark of many other neurodegenerative diseases such as the SOD-1 aggregates in ALS (amyotrophic lateral sclerosis).There are two main protein degradation pathways in eukaryotic cells:the ubiquitin-proteosome pathway and the autophagy-lysosome pathway. Autophagy is, when compared to ubiquitin pathway, more effective in turn over the above mentioned aggregated proteins in neurodegenerative disease. In accordance with this, the mutation or deficient of autophagy related genes (ATG) in neurons could directly course neurodegenerative disease.Omi, also known as HtrA2, is a serine protease that was originally identified as a pro-apoptotic protein. Like Smac/Diablo, it antagonizes IAP proteins when released into the cytosol upon apoptotic stimulation. Loss of its protease activity in mnd2 (motor neuron degeneration 2) mice or Omi KO mice are associated with neurodegeneration. However, the detailed mechanisms by which Omi regulates the pathogenesis of neurodegenerative disease remain largely unknown.We report here that Omi participates in the above mentioned pivotal cellular degradation process:autophagy. Omi activates autophagy through digestion of Hax-1, a Bcl-2 family-related protein that represses autophagy in a Beclin-1 (mammalian homolog of yeast ATG6)-dependent pathway. Moreover, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T a-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Knockdown of Omi decreases the basal level of autophagy and increases the level of the above target proteins. Furthermore, S276C Omi, the protease-defective mutant found in mnd2 mice, fails to regulate autophagy. Increased autophagy substrates and the formation of aggregate structures are observed in the brains of mnd2 mice.These results identify Omi as a novel regulator of autophagy and suggest that Omi might play important roles in the cellular quality control of proteins involved in neurodegenerative diseases.