Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo

J Biol Chem. 2010 Jun 4;285(23):17648-61. doi: 10.1074/jbc.M110.100867. Epub 2010 Mar 31.


Alpha-synuclein (a-Syn), a protein implicated in Parkinson disease, contributes significantly to dopamine metabolism. a-Syn binding inhibits the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Phosphorylation of TH stimulates its activity, an effect that is reversed by protein phosphatase 2A (PP2A). In cells, a-Syn overexpression activates PP2A. Here we demonstrate that a-Syn significantly inhibited TH activity in vitro and in vivo and that phosphorylation of a-Syn serine 129 (Ser-129) modulated this effect. In MN9D cells, a-Syn overexpression reduced TH serine 19 phosphorylation (Ser(P)-19). In dopaminergic tissues from mice overexpressing human a-Syn in catecholamine neurons only, TH-Ser-19 and TH-Ser-40 phosphorylation and activity were also reduced, whereas PP2A was more active. Cerebellum, which lacks excess a-Syn, had PP2A activity identical to controls. Conversely, a-Syn knock-out mice had elevated TH-Ser-19 phosphorylation and activity and less active PP2A in dopaminergic tissues. Using an a-Syn Ser-129 dephosphorylation mimic, with serine mutated to alanine, TH was more inhibited, whereas PP2A was more active in vitro and in vivo. Phosphorylation of a-Syn Ser-129 by Polo-like-kinase 2 in vitro reduced the ability of a-Syn to inhibit TH or activate PP2A, identifying a novel regulatory role for Ser-129 on a-Syn. These findings extend our understanding of normal a-Syn biology and have implications for the dopamine dysfunction of Parkinson disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine / metabolism
  • Humans
  • In Vitro Techniques
  • Lentivirus / metabolism
  • Mice
  • Mice, Transgenic
  • Mutagenesis
  • Neurotransmitter Agents / metabolism
  • Parkinson Disease / metabolism
  • Phosphorylation
  • Protein Phosphatase 2 / chemistry*
  • Serine / chemistry*
  • Tyrosine / chemistry
  • Tyrosine 3-Monooxygenase / chemistry*
  • alpha-Synuclein / chemistry*


  • Neurotransmitter Agents
  • alpha-Synuclein
  • Tyrosine
  • Serine
  • Tyrosine 3-Monooxygenase
  • Protein Phosphatase 2
  • Dopamine