Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies

alpha-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson's disease. Highly phosphorylated and abnormally aggregated alpha-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated alpha-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most alpha-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated alpha-synuclein in Lewy bodies of patients with Parkinson's disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in alpha-synucleinopathy. Consequently, this review focuses on the pathogenic impact of alpha-synuclein phosphorylation and its kinases during the neurodegeneration process in alpha-synucleinopathy.