α-synuclein degradation dynamics and the evaluation of a new mouse model in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease around the world. Formation of Lewy bodies is one of the hallmarks of PD pathogenesis. α-synuclein (α-syn) is the major component of Lewy bodies and its degradation is considered as a potential therapeutic approach of PD. Polo-like kinase 2 (PLK2) is a kinase that phosphorylates α-syn at Ser129 site and its level is regulated by ubiquitin-proteasome system (UPS). The PLK2 is reported to induce α-syn degradation through a phosphorylation-dependent pathway and the raised levels of PLK2 increases the level of pSer129 α-syn together with a decreased α-syn level. In HEK 293T, SH-SY5Y cells and primary culture of mouse cortical neurons, the PLK2 and pSer129 α-syn levels were significantly increased upon proteasomal inhibition following by the decrease in α-syn levels. Although autophagy was reported to be responsible for the PLK2 induced α-syn degradation, the PLK2, pSer129 α-syn and α-syn levels were not rescued by autophagic inhibition. Interestingly, the co-treatments of proteasome and autophagy inhibitors resulted in even lower pSer129 α-syn and α-syn levels in HEK 293T and SH-SY5Y cells. Pathways other than UPS and autophagy may be involved in the PLK2 induced α-syn degradation. New mouse models that conditionally express human α-syn or α-syn-CL1 were created by applying Cre-loxP approach. The expressions of α-syn or α-syn-CL1 were achieved in different parts of brains by crossbreeding the mouse models with Nestin^Cre mouse line. In addition, the dopaminergic neuronal loss was also observed in those mice expressing α-syn-CL1. Therefore, other hallmarks of PD pathogenesis such as motor symptoms, formation of Lewy bodies and dopamine levels may be further revealed in these mouse models to evaluate their abilities in mimicking PD pathogenesis.

Date of Award	2021
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Kenny K CHUNG (Supervisor)