Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

Abstract

Abstract Post-translational protein modifications play an important role in generating the large diver- sity of the proteome in comparison to the relatively small number of genes; phosphorylation being the most widespread. Phosphorylation of proteins regulates important molecular- switches for several cellular events and abnormal phosphorylation events are associated in many neurodegenerative diseases. In Parkinson’s disease (PD) the main hallmark is the accumulation of cytoplasmic inclusions, Lewy bodies (LBs), consisting of α-synuclein (α-Syn) and ubiquitin. There’s another key observation which is increasingly gaining promi- nence is a modified-form of α-Syn; the phospho α-Syn serine129 (pSyn). The significance of pSyn has gained importance in PD because its accumulation is distinctly enhanced in the diseased condition. The revelation of the involvement of pSyn on α-Syn aggregation, LB formation and neurotoxicity is crucial to understanding the pathogenesis and progression of PD. Since some in vitro and in vivo studies have indicated that pSyn is an early event pre- ceding apoptosis, some important questions now needs to be explored in reference to the physiological functions regulated by phosphorylation, such as dopamine synthesis, vesicle mobilization, regulation of synaptic proteins, and synaptic plasticity. An investigation of the role of enzymes on the phosphorylation and clearance of α-Syn and region-specific suscep- tibility is required to be determined; to identify viable targets for new therapeutics.