α-Synuclein phosphorylation as a therapeutic target in Parkinson's disease

Phosphorylation is a key post-translational modification necessary for normal cellular signaling and, therefore, lies at the heart of cellular function. In neurodegenerative disorders, abnormal hyperphosphorylation of pathogenic proteins is a common phenomenon that contributes in important ways to the disease process. A prototypical protein that is hyperphosphorylated in the brain is alpha-synuclein (alpha-syn) - found in Lewy bodies and Lewy neurites - the pathological hallmarks of Parkinson's disease (PD) and other alpha-synucleinopathies. The genetic linkage of alpha-syn to PD as well as its pathological association in both genetic and sporadic cases have made it the primary protein of interest. In understanding how alpha-syn dysfunction occurs, increasing focus is being placed on its abnormal aggregation and the contribution of phosphorylation to this process. Studies of both the kinases and phosphatases that regulate alpha-syn phosphorylation are beginning to reveal the roles of this post-translational modification in disease pathogenesis. Modulation of alpha-syn phosphorylation may ultimately prove to be a viable strategy for disease-modifying therapeutic interventions. In this review, we explore mechanisms related to alpha-syn phosphorylation, its biophysical and functional consequences, and its role in neurodegeneration.