Phosphorylation of α-synuclein in relation to the pathogenesis and treatment of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder that is primarily sporadic, but familial-linked PD cases have also been found. The first reported gene mutation linked to PD is α-synuclein (α-syn). Studies have shown that mutations, increased expression, or abnormal processing of α-syn contribute to PD, but it is believed that multiple mechanisms are involved. One of the contributing factors is post-translational modification such as phosphorylation of α-syn at Ser129 by G-protein-coupled receptor kinases (GRKs), casein kinase 2 (CK2), and polo-like kinase 2 (PLK2). Another crucial contributing factor to PD pathogenesis is oxidative and nitrosative stress. In this study, I found that GRK6 and CK2 can be S-nitrosylated by nitric oxide (NO) both in vitro and in vivo. S-nitrosylation of GRK6 and CK2 enhanced their kinase activity towards the phosphorylation of α-syn at Ser129. In an A53T α-syn transgenic mouse model of PD, I found that increased GRK6 and CK2 S-nitrosylation were observed in an age-dependent manner, and it was associated with an increased level of pSer129 α-syn. Deleting neuronal nitric oxide synthase in A53T α-syn transgenic mice reduced the levels pSer129 α-syn and α-syn in an age-dependent manner. The results provide a novel mechanism of how NO through S-nitrosylation of GRK6 and CK2 can enhance the phosphorylation of pSer129 α-syn and contribute to PD pathogenesis in the context of aging. On the other hand, PLK2 mediated α-syn degradation through the autophagy-lysosomal pathway by phosphorylating α-syn at Ser129. I reported that inhibition of the ubiquitin-proteasomal pathway causes the accumulation of PLK2 and enhanced degradation of α-syn. By administrating a low dosage of Proteasome Inhibitor I, the level of soluble and insoluble α-syn in A53T α-syn transgenic mice dropped to its half. The modulation of α-syn phosphorylation can hence be a possible target in searching for treatment of PD.

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