Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates

Neuroscience. 2007 Jan 19;144(2):743-53. doi: 10.1016/j.neuroscience.2006.09.052. Epub 2006 Nov 13.


Recombinant adeno-associated viral (rAAV) vector-mediated overexpression of alpha-synuclein (alphaSyn) protein has been shown to cause neurodegeneration of the nigrostriatal dopaminergic pathway in rodents and primates. Using serotype-2 rAAV vectors, we recently reported the protective effect of Parkin on alphaSyn-induced nigral dopaminergic neurodegeneration in a rat model. Here we investigated the neuronal specificity of alphaSyn toxicity and the effect of Parkin co-expression in a primate model. We used another serotype (type-1) of AAV vector that was confirmed to deliver genes of interest anterogradely and retrogradely to neurons in rats. The serotype-1 rAAV (rAAV1) carrying alphaSyn cDNA (rAAV1-alphaSyn), and a cocktail of rAAV1-alphaSyn and rAAV1 carrying parkin cDNA (rAAV1-parkin) were unilaterally injected into the striatum of macaque monkeys, resulting in protein expression in striatonigral GABAergic and nigrostriatal dopaminergic neurons. Injection of rAAV1-alphaSyn alone decreased tyrosine hydroxylase immunoreactivity in the striatum compared with the contralateral side injected with a cocktail of rAAV1-alphaSyn and rAAV1-parkin. Immunostaining of striatonigral GABAergic neurons was similar on both sides. Overexpression of Parkin in GABAergic neurons was associated with less accumulation of alphaSyn protein and/or phosphorylation at Ser129 residue. Our results suggest that the toxicity of accumulated alphaSyn is not induced in non-dopaminergic neurons and that the alphaSyn-ablating effect of Parkin is exerted in virtually all neurons in primates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Cell Count
  • Dependovirus / physiology
  • Fluorescent Antibody Technique / methods
  • Gene Expression / physiology*
  • Genetic Vectors / physiology
  • Green Fluorescent Proteins / metabolism
  • Macaca mulatta / metabolism*
  • Male
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Serine / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • alpha-Synuclein / metabolism*


  • Nerve Tissue Proteins
  • alpha-Synuclein
  • Green Fluorescent Proteins
  • Serine
  • Ubiquitin-Protein Ligases
  • parkin protein