title: Phosphorylation of α-synuclein is crucial in compensating for proteasomal dysfunction.
abstract: α-Synuclein can be degraded by both the ubiquitin-proteasomal system and the chaperone-lysosomal system. However, the switching mechanism between the two pathways is not clearly understood. In our study, we investigated the mutual association between the binding of α-synuclein to heat shock cognate 70 and the lysosomal translocation of α-synuclein. Tyrosine phosphorylation of Y136 on α-synuclein increased when it bound to heat shock protein 70. We also found that tyrosine phosphorylation of α-synuclein can be regulated by focal adhesion kinase pp125 and protein tyrosine phosphatase 1B. Furthermore, protein tyrosine phosphatase 1B inhibitor protected dopaminergic neurons against cell death and rescued rotarod performance in a Parkinson's disease animal model. This study provides evidence that the regulation of Y136 phosphorylation of α-synuclein can improve behavioral performance and protect against neuronal death by promoting the turnover of lysosomal degradation of α-synuclein. As a result, protein tyrosine phosphatase 1B inhibitor may be used as a potential therapeutic agent against Parkinson's disease.
authors: Department of Pharmacology, College of Medicine, Seoul National University, Seoul 110-799, South Korea.
authors: Hee Soon
authors: HS
authors: Choi
authors: Hyunjeong
authors: H
authors: Liew
authors: Ahram
authors: A
authors: Jang
authors: Yun-Mi
authors: YM
authors: Kim
authors: Hilal
authors: H
authors: Lashuel
authors: Yoo-Hun
authors: YH
authors: Suh
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D010300:Parkinson Disease / Q000201:enzymology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors; D014443:Tyrosine / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D050883:HSC70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D046988:Proteasome Endopeptidase Complex