Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates.
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.
Yasuda
T
T
Research Institute for Diseases of Old Ages, Juntendo University School of Medicine, Tokyo, Japan.
Miyachi
S
S
Kitagawa
R
R
Wada
K
K
Nihira
T
T
Ren
Y-R
YR
Hirai
Y
Y
Ageyama
N
N
Terao
K
K
Shimada
T
T
Takada
M
M
Mizuno
Y
Y
Mochizuki
H
H
D000818:Animals; D001921:Brain / Q000166:cytology; D002452:Cell Count; D000229:Dependovirus / Q000502:physiology; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000502:physiology*; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D012694:Serine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein