The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease

Departments of *Molecular Genetics and Microbiology and
^†Neurosciences, University of Florida College of Medicine, Gainesville, FL 32610

Communicated by Kenneth I. Berns, University of Florida College of Medicine, Gainesville, FL, November 21, 2007 (received for review July 24, 2007)

Abstract

Studies have shown that α-synuclein (α-syn) deposited in Lewy bodies in brain tissue from patients with Parkinson disease (PD) is extensively phosphorylated at Ser-129. We used recombinant Adeno-associated virus (rAAV) to overexpress human wild-type (wt) α-syn and two human α-syn mutants with site-directed replacement of Ser-129 to alanine (S129A) or to aspartate (S129D) in the nigrostriatal tract of the rat to investigate the effect of Ser-129 phosphorylation state on dopaminergic neuron pathology. Rats were injected with rAAV2/5 vectors in the substantia nigra pars compacta (SNc) on one side of the brain; the other side remained as a nontransduced control. The level of human wt or mutant α-syn expressed on the injected side was about four times the endogenous rat α-syn. There was a significant reduction of dopaminergic neurons in the SNc and dopamine (DA) and tyrosine hydroxylase (TH) levels in the striatum of all S129A-treated rats as early as 4 wk postinjection. Nigral DA pathology occurred more slowly in the wt-injected animals, but by 26 wk the wt α-syn group lost nigral TH neurons equivalent to the mutated S129A group at 8 wk. In stark contrast, we did not observe any pathological changes in S129D-treated animals. Therefore, the nonphosphorylated form of S129 exacerbates α-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates α-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.

Footnotes

^‡To whom correspondence should be addressed. E-mail: muzyczka{at}mgm.ufl.edu
Author contributions: O.S.G., S.L., and N.M. designed research; O.S.G., S.L., L.F.S., W.C., G.K., and F.P.M. performed research; O.S.G., R.J.M., and N.M. analyzed data; and O.S.G. and N.M. wrote the paper.
Conflict of interest statement: N.M. is an inventor of patents related to recombinant AAV technology and owns equity in a gene therapy company that is commercializing AAV for gene therapy applications.