title: Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent protein phosphatase 2A activation.
abstract: Phospho-Ser129 α-synuclein is the modified form of α-synuclein that occurs most frequently within Parkinson's disease pathological inclusions. Here we demonstrate that the antidiabetic drug metformin significantly reduces levels of phospho-Ser129 α-synuclein and the ratio of phospho-Ser129 α-synuclein to total α-synuclein. This effect was documented in vitro in SH-SY5Y and HeLa cells as well as in primary cultures of hippocampal neurons. In vitro work also elucidated the mechanisms underlying metformin's action. Following metformin exposure, decreased phospho-Ser129 α-synuclein was not strictly dependent on induction of AMP-activated protein kinase, a primary target of the drug. On the other hand, metformin-induced phospho-Ser129 α-synuclein reduction was consistently associated with inhibition of mammalian target of rapamycin (mTOR) and activation of protein phosphatase 2A (PP2A). Evidence supporting a key role of mTOR/PP2A signaling included the finding that, similar to metformin, the canonical mTOR inhibitor rapamycin was capable of lowering the ratio of phospho-Ser129 α-synuclein to total α-synuclein. Furthermore, no decrease in phosphorylated α-synuclein occurred with either metformin or rapamycin when phosphatase activity was inhibited, supporting a direct relationship between mTOR inhibition, PP2A activation and protein dephosphorylation. A final set of experiments confirmed the effectiveness of metformin in vivo in wild-type C57BL/6 mice. Addition of the drug to food or drinking water lowered levels of phospho-Ser129 α-synuclein in the brain of treated animals. These data reveal a new mechanism leading to α-synuclein dephosphorylation that could be targeted for therapeutic intervention by drugs like metformin and rapamycin.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: B I
authors.initials: BI
authors.lastname: Pérez-Revuelta
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Hettich
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ciociaro
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Rotermund
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: P J
authors.initials: PJ
authors.lastname: Kahle
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Krauss
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: D A
authors.initials: DA
authors.lastname: Di Monte
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005865:Gestational Age; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D047428:Protein Kinase Inhibitors; D051844:alpha-Synuclein; D012694:Serine; D008687:Metformin; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2