| http://purl.uniprot.org/citations/25813876 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/25813876 | http://www.w3.org/2000/01/rdf-schema#comment | "Alpha-synuclein (α-Syn) is a major component of Lewy bodies, a pathological feature of Parkinson's and other neurodegenerative diseases collectively known as synucleinopathies. Among the possible mechanisms of α-Syn-mediated neurotoxicity is interference with cytoprotective pathways such as insulin signaling. Insulin receptor substrate (IRS)-1 is a docking protein linking IRs to downstream signaling pathways such as phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K)1; the latter exerts negative feedback control on insulin signaling, which is impaired in Alzheimer's disease. Our previous study found that α-Syn overexpression can inhibit protein phosphatase (PP)2A activity, which is involved in the protective mechanism of insulin signaling. In this study, we found an increase in IRS-1 phosphorylation at Ser636 and decrease in tyrosine phosphorylation, which accelerated IRS-1 turnover and reduced insulin-Akt signaling in α-Syn-overexpressing SK-N-SH cells and transgenic mice. The mTOR complex (C)1/S6K1 blocker rapamycin inhibited the phosphorylation of IRS-1 at Ser636 in cells overexpressing α-Syn, suggesting that mTORC1/S6K1 activation by α-Syn causes feedback inhibition of insulin signaling via suppression of IRS-1 function. α-Syn overexpression also inhibited PP2A activity, while the PP2A agonist C2 ceramide suppressed both S6K1 activation and IRS-1 Ser636 phosphorylation upon α-Syn overexpression. Thus, α-Syn overexpression negatively regulated IRS-1 via mTORC1/S6K1 signaling while activation of PP2A reverses this process. These results provide evidence for a link between α-Syn and IRS-1 that may represent a novel mechanism for α-Syn-associated pathogenesis."xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.biocel.2015.03.006"xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/author | "Gao S."xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/author | "Wang X."xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/author | "Yang H."xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/author | "Gao G."xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/author | "Duan C."xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/date | "2015"xsd:gYear |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/name | "Int J Biochem Cell Biol"xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/pages | "25-33"xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/title | "Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling."xsd:string |
| http://purl.uniprot.org/citations/25813876 | http://purl.uniprot.org/core/volume | "64"xsd:string |
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