QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 19 July 2005
doi: 10.1242/jcs.02481

This Article Figures Only Full Text Full Text (PDF) An erratum has been published OA All Versions of this Article: jcs.02481v1 118/15/3523    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Peng, X. M. Articles by Perez, R. G. Search for Related Content PubMed PubMed Citation Articles by Peng, X. M. Articles by Perez, R. G. Social Bookmarking                         What's this?

-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells

Xiangmin M. Peng^1,*, Roya Tehranian^1,, Paula Dietrich^3,, Leonidas Stefanis^3,4,¶ and Ruth G. Perez^1,2,**

¹ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
² Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
³ Department of Neurology, Columbia University, New York, NY, 10027-6902, USA
⁴ Department of Pathology, Columbia University, New York, NY, 10027-6902, USA

^** Author for correspondence (e-mail: perezrg{at}pitt.edu)

Accepted 10 May 2005

-Synuclein is an abundant presynaptic protein implicated in neuronal plasticity and neurodegenerative diseases. Although the function of -synuclein is not thoroughly elucidated, we found that -synuclein regulates dopamine synthesis by binding to and inhibiting tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis. Understanding -synuclein function in dopaminergic cells should add to our knowledge of this key protein, which is implicated in Parkinson's disease and other disorders. Herein, we report a mechanism by which -synuclein diminishes tyrosine hydroxylase phosphorylation and activity in stably transfected dopaminergic cells. Short-term regulation of tyrosine hydroxylase depends on the phosphorylation of key seryl residues in the amino-terminal regulatory domain of the protein. Of these, Ser40 contributes significantly to tyrosine hydroxylase activation and dopamine synthesis. We observed that -synuclein overexpression caused reduced Ser40 phosphorylation in MN9D cells and inducible PC12 cells. Ser40 is phosphorylated chiefly by the cyclic AMP-dependent protein kinase PKA and dephosphorylated almost exclusively by the protein phosphatase, PP2A. Therefore, we measured the impact of -synuclein overexpression on levels and activity of PKA and PP2A in our cells. PKA was unaffected by -synuclein. PP2A protein levels also were unchanged, however, the activity of PP2A increased in parallel with -synuclein expression. Inhibition of PP2A dramatically increased Ser40 phosphorylation only in -synuclein overexpressors in which -synuclein was also found to co-immunoprecipitate with PP2A. Together the data reveal a functional interaction between -synuclein and PP2A that leads to PP2A activation and underscores a key role for -synuclein in protein phosphorylation.

Key words: MN9D, PC12, dopamine, PP2A, Parkinson's disease

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				V. L. Sousa, S. Bellani, M. Giannandrea, M. Yousuf, F. Valtorta, J. Meldolesi, and E. Chieregatti {alpha}-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics Mol. Biol. Cell, August 15, 2009; 20(16): 3725 - 3739. [Abstract] [Full Text] [PDF]

				J. Wang, H. Lou, C. J. Pedersen, A. D. Smith, and R. G. Perez 14-3-3{zeta} Contributes to Tyrosine Hydroxylase Activity in MN9D Cells: LOCALIZATION OF DOPAMINE REGULATORY PROTEINS TO MITOCHONDRIA J. Biol. Chem., May 22, 2009; 284(21): 14011 - 14019. [Abstract] [Full Text] [PDF]

				O. S. Gorbatyuk, S. Li, L. F. Sullivan, W. Chen, G. Kondrikova, F. P. Manfredsson, R. J. Mandel, and N. Muzyczka The phosphorylation state of Ser-129 in human {alpha}-synuclein determines neurodegeneration in a rat model of Parkinson disease PNAS, January 15, 2008; 105(2): 763 - 768. [Abstract] [Full Text] [PDF]

				C. Y. Chung, J. B. Koprich, S. Endo, and O. Isacson An Endogenous Serine/Threonine Protein Phosphatase Inhibitor, G-Substrate, Reduces Vulnerability in Models of Parkinson's Disease J. Neurosci., August 1, 2007; 27(31): 8314 - 8323. [Abstract] [Full Text] [PDF]

				D. Zhang, A. Kanthasamy, Y. Yang, V. Anantharam, and A. Kanthasamy Protein Kinase C{delta} Negatively Regulates Tyrosine Hydroxylase Activity and Dopamine Synthesis by Enhancing Protein Phosphatase-2A Activity in Dopaminergic Neurons J. Neurosci., May 16, 2007; 27(20): 5349 - 5362. [Abstract] [Full Text] [PDF]

				K. E. Larsen, Y. Schmitz, M. D. Troyer, E. Mosharov, P. Dietrich, A. Z. Quazi, M. Savalle, V. Nemani, F. A. Chaudhry, R. H. Edwards, et al. {alpha}-Synuclein Overexpression in PC12 and Chromaffin Cells Impairs Catecholamine Release by Interfering with a Late Step in Exocytosis. J. Neurosci., November 15, 2006; 26(46): 11915 - 11922. [Abstract] [Full Text] [PDF]

				S. A. Austin, A. M. Floden, E. J. Murphy, and C. K. Combs {alpha}-Synuclein Expression Modulates Microglial Activation Phenotype J. Neurosci., October 11, 2006; 26(41): 10558 - 10563. [Abstract] [Full Text] [PDF]