S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
Studies on the role of phosphorylation of alpha-synuclein in alpha-synuclein degradation pathway
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과 약리학 전공, 2013. 8. 김용식.
- 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.