Nigrostriatal {alpha}-synucleinopathy induced by viral vector-mediated overexpression of human {alpha}-synuclein: A new primate model of Parkinson's disease.

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Abstract

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.

Detaljer

Författare
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Neurovetenskaper
Originalspråkengelska
Sidor (från-till)2884-2889
TidskriftProceedings of the National Academy of Sciences
Volym100
Utgivningsnummer5
StatusPublished - 2003
PublikationskategoriForskning
Peer review utfördJa