α-Synuclein Deletion Leads to Hyposmia: due to Defective Autophagy Induced by Abnormal PI3K/mTOR Signaling Pathway in...

α-Synuclein has been the center of focus in understanding synucleinopathies such as Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, dementia with Lewy bodies, for decades. Most researches focus on its pathology. However, its physiological function remains elusive, especially in olfactory system, one of the original sites to find α-synuclein accumulation in Parkinson's disease. In the present study, α-synuclein knockout (KO) mice were employed to study its physiological function. KO mice exhibited olfaction impairment with cell apoptosis in olfactory bulb. To identify molecules underlying olfactory dysfunction, we employed proteomics based on isobaric tags for relative and absolute quantification (iTRAQ). 188 differentially expressed proteins were identified between KO mice and its littermate control of wildtype mice. Bioinformatic analysis highlighted Phosphatidyl-inositol-3-kinase (PI3K) pathway. Hence, we examined its activation and found that both PI3K and its downstream, protein kinase B(AKT) is hyperactivated with α-synuclein deficiency. Mammalian target of Rapamycin (mTOR), a switch of autophagy, was activated followed by uncoordinated 51-like kinase 1, the autophagy initiator, inhibition. The specific substrate of autophagy, P62 was accumulated, indicating that autophagy was blocked. This blockade of autophagy led to Caspase 8 mediated apoptosis characterized by an increased ratio of B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) to BCL-2 (BAX/BCL-2), reduced mitochondrial complex I activity, and decreased mitochondrial membrane potential. To summarize, α-synuclein played roles in maintaining the normal structure and function of olfactory system. α-Synuclein deletion induced Caspase 8 mediated apoptosis due to the defective autophagy by PI3K/mTOR hyperactivation.