Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson's disease.
We used a high-titer recombinant adeno-associated virus (rAAV) vector to express WT or mutant human alpha-synuclein in the substantia nigra of adult marmosets. The alpha-synuclein protein was expressed in 90-95% of all nigral dopamine neurons and distributed by anterograde transport throughout their axonal and dendritic projections. The transduced neurons developed severe neuronal pathology, including alpha-synuclein-positive cytoplasmic inclusions and granular deposits; swollen, dystrophic, and fragmented neuritis; and shrunken and pyknotic, densely alpha-synuclein-positive perikarya. By 16 wk posttransduction, 30-60% of the tyrosine hydroxylase-positive neurons were lost, and the tyrosine hydroxylase-positive innervation of the caudate nucleus and putamen was reduced to a similar extent. The rAAV-alpha-synuclein-treated monkeys developed a type of motor impairment, i.e., head position bias, compatible with this magnitude of nigrostriatal damage. rAAV vector-mediated alpha-synuclein gene transfer provides a transgenic primate model of nigrostriatal alpha-synucleinopathy that is of particular interest because it develops slowly over time, like human Parkinson's disease (PD), and expresses neuropathological features (alpha-synuclein-positive inclusions and dystrophic neurites, in particular) that are similar to those seen in idiopathic PD. This model offers new opportunities for the study of pathogenetic mechanisms and exploration of new therapeutic targets of particular relevance to human PD.
Kirik
Deniz
D
Wallenberg Neuroscience Center, Department of Physiological Sciences, Division of Neurobiology, Lund University, BMC A11, 221 84 Lund, Sweden. deniz.kirik@mphy.lu.se
Annett
Lucy E
LE
Burger
Corinna
C
Muzyczka
Nicholas
N
Mandel
Ronald J
RJ
Björklund
Anders
A
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D002144:Callithrix; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D051843:Synucleins; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein
D000662:Amphetamines; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine