title: Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling.
abstract: 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.
authors: Center for Parkinson's Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology, Capital Medical University, Beijing 100069, China.
authors: Shanshan
authors: S
authors: Gao
authors: Center for Parkinson's Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology, Capital Medical University, Beijing 100069, China.
authors: Chunli
authors: C
authors: Duan
authors: Center for Parkinson's Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology, Capital Medical University, Beijing 100069, China.
authors: Ge
authors: G
authors: Gao
authors: Center for Parkinson's Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology, Capital Medical University, Beijing 100069, China.
authors: Xiaoming
authors: X
authors: Wang
authors: Center for Parkinson's Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology, Capital Medical University, Beijing 100069, China. Electronic address: huiyang@ccmu.edu.cn.
authors: Hui
authors: H
authors: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D046912:Multiprotein Complexes; D051844:alpha-Synuclein; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D054648:Protein Phosphatase 2
keywords: Alpha-synuclein (α-Syn); Insulin receptor substrate 1 (IRS-1); Mammalian target of rapamycin complex 1 (mTORC1); Protein phosphatase 2A (PP2A); p70 Ribosomal S6 kinase 1 (S6K1)