The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson's disease: a review of in vivo models

Parkinson's disease is the most common neuro-degenerative movement disorder. The motor impairments of Parkinson's disease are caused by the loss of dopaminergic neurons in the substantia nigra and associated with the appearance of fibrillar aggregates of alpha-synuclein (alpha-syn) called Lewy bodies. Approximately 90% of alpha-syn deposited in Lewy bodies is phosphorylated at serine 129 (Ser129). In contrast, only 4% or less of total alpha-syn is phosphorylated at this residue in the normal brain. This suggests that the accumulation of Ser129-phosphorylated alpha-syn leads to the formation of Lewy bodies and dopaminergic neurodegeneration in Parkinson's disease. Our laboratory and others have performed experiments using in vivo models of Parkinson's disease to elucidate the role of increased Ser129 phosphorylation in alpha-syn neurotoxicity. However, there has been a lack of consistency among these models. In this review, we summarize the main findings regarding the relationship between Ser129 phosphorylation and alpha-syn neurotoxicity, and examine the differences among models. We further discuss the role of Ser129 phosphorylation in alpha-syn aggregation and the future directions to test the potential of Ser129 phosphorylation as a therapeutic target for slowing the progression of Parkinson's disease.