PMID- 24810045
OWN - NLM
STAT- MEDLINE
DCOM- 20141021
LR  - 20211203
IS  - 2041-4889 (Electronic)
VI  - 5
IP  - 5
DP  - 2014 May 8
TI  - Metformin lowers Ser-129 phosphorylated alpha-synuclein levels via mTOR-dependent 
      protein phosphatase 2A activation.
PG  - e1209
LID - 10.1038/cddis.2014.175 [doi]
AB  - Phospho-Ser129 alpha-synuclein is the modified form of alpha-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 alpha-synuclein and the ratio of phospho-Ser129 alpha-synuclein to total 
      alpha-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 alpha-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 alpha-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 
      alpha-synuclein to total alpha-synuclein. Furthermore, no decrease in phosphorylated 
      alpha-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 alpha-synuclein in 
      the brain of treated animals. These data reveal a new mechanism leading to 
      alpha-synuclein dephosphorylation that could be targeted for therapeutic intervention 
      by drugs like metformin and rapamycin.
FAU - Perez-Revuelta, B I
AU  - Perez-Revuelta BI
AD  - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
FAU - Hettich, M M
AU  - Hettich MM
AD  - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
FAU - Ciociaro, A
AU  - Ciociaro A
AD  - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
FAU - Rotermund, C
AU  - Rotermund C
AD  - German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany.
FAU - Kahle, P J
AU  - Kahle PJ
AD  - German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany.
FAU - Krauss, S
AU  - Krauss S
AD  - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
FAU - Di Monte, D A
AU  - Di Monte DA
AD  - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140508
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (alpha-Synuclein)
RN  - 452VLY9402 (Serine)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Enzyme Activation
MH  - Gestational Age
MH  - HeLa Cells
MH  - Hippocampus/*drug effects/embryology/enzymology/pathology
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neurons/*drug effects/enzymology/pathology
MH  - Phosphorylation
MH  - Primary Cell Culture
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Phosphatase 2/*metabolism
MH  - Serine
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Time Factors
MH  - Transfection
MH  - alpha-Synuclein/genetics/*metabolism
PMC - PMC4047877
EDAT- 2014/05/09 06:00
MHDA- 2014/10/22 06:00
PMCR- 2014/05/01
CRDT- 2014/05/10 06:00
PHST- 2013/12/02 00:00 [received]
PHST- 2014/03/10 00:00 [revised]
PHST- 2014/03/17 00:00 [accepted]
PHST- 2014/05/10 06:00 [entrez]
PHST- 2014/05/09 06:00 [pubmed]
PHST- 2014/10/22 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - cddis2014175 [pii]
AID - 10.1038/cddis.2014.175 [doi]
PST - epublish
SO  - Cell Death Dis. 2014 May 8;5(5):e1209. doi: 10.1038/cddis.2014.175.