Neurobiology
Serine 129 Phosphorylation Reduces the Ability of α-Synuclein to Regulate Tyrosine Hydroxylase and Protein Phosphatase 2A in Vitro and in Vivo*

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α-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.

Enzyme Catalysis
Neurological Diseases
Neuron
Neurotransmitters
PP2A
Dopamine
MN9D Cells
Lentivirus
Null Mice
Transgenic Mice

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This work is dedicated to M. J. Fox, R. Byer, and J. Cordy and in memory of L. “Rusty” Lanelli.

*

This work was supported, in whole or in part, by National Institutes of Health Grants NS42094 (to R. G. P. with a supplement provided for S. E. M. (NINDS)) and GM47291 (to S. C. D.). This work was also supported by the China Scholarship Council (to H. L.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

1

These authors contributed equally to this work.

2

Present address: Institute of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.

3

Present address: Dept. of Neurology, Fudan University Huashan Hospital, 12 Wulumuqi Zhong Rd., Shanghai 200040, China.

4

Present address: Dept. of Neurology, University of Michigan School of Medicine, 109 Zina Pitcher Pl., Ann Arbor, MI 48109.