Abstract
Parkinson's disease (PD) is a neurodegenerative disorder caused by the degeneration of dopaminergic neurons in the brain stem. PD is mostly sporadic, but familial PD (FPD) cases are recorded in different studies. The first gene mutation that is linked to FPD is α-synuclein (α-syn). It was then found that α-syn is also accumulated in Lewy body (LB), a classical pathological hallmark in PD patients. Different studies have shown that α-syn accumulation and aggregation can be a crucial factor contributing to the degeneration of dopaminergic neurons in PD. α-syn has been found to be degraded by the ubiquitin proteasomal system (UPS) and autophagy-lysosomal pathway (ALP). In this study, we initially explored how α-syn phosphorylation by GRK6, PLK2 and CK2α would facilitate its degradation in relation to the UPS or ALP. Unexpectedly, we found that the degradation of α-syn through PLK2 phosphorylation could be modulated by UPS and ALP in a novel mechanism. Specially, attenuation of UPS could increase the amount of PLK2 and then could facilitate the phosphorylation and degradation of α-syn through ALP. To test this further in vivo, we attenuate the proteasomal activity in a well-established A53T α-syn transgenic PD mouse model. We found that attenuation of proteasomal activity in the A53T α-syn transgenic mice could reduce the accumulation of α-syn in the striatum and midbrain. Based on our results, this study provides a new insight into how α-syn is degraded through the UPS and ALP.