Studies on the role of phosphorylation of alpha-synuclein in alpha-synuclein degradation pathway

Abstract

α-Synuclein (α-SYN) has been characterized as a heat-stable and aggregation-prone protein that can be degraded by both the ubiquitin-proteasomal pathway and the chaperone-lysosomal pathway. However, the switching mechanism between the two pathways is not well understood. In my study, I investigated the increase of the binding of α-SYN to heat shock protein 70 cognate (HSC70) and the lysosomal translocation of α-SYN. Tyrosine phosphorylation at Y136 of α-SYN increased its binding to HSC70. I also found that Y136 phosphorylation of α-SYN can be regulated by the focal adhesion kinase pp125 (FAK) and protein tyrosine phosphatase 1B (PTP1B). Furthermore, a PTP1B inhibitor prevented the accumulation of α-SYN in SH-SY5Y cells by increasing α-SYN translocation into the lysosome, protected dopaminergic neurons against cell death and rescued Rotarod performance in a Parkinsons disease (PD) model. I provide evidence that the regulation of the phosphorylation of α-SYN at Y136 can improve behavioral performance and protect dopaminergic neurons against cell death through enhanced lysosomal degradation of α-SYN.