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

Kirik, Deniz LU ; Annett, Lucy E.; Burger, Corinna; Muzyczka, Nicholas; Mandel, Ronald J. and Björklund, Anders LU (2003) In Proceedings of the National Academy of Sciences 100(5). p.2884-2889
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
100
issue
5
pages
2884 - 2889
publisher
National Acad Sciences
external identifiers
  • wos:000181365000127
  • pmid:12601150
  • scopus:0345269757
ISSN
1091-6490
DOI
10.1073/pnas.0536383100
language
English
LU publication?
yes
id
38f1ed3c-fdbd-4e29-b4f9-5a779a194fca (old id 112219)
date added to LUP
2007-06-26 10:35:58
date last changed
2018-09-16 03:30:39
@article{38f1ed3c-fdbd-4e29-b4f9-5a779a194fca,
  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.},
  author       = {Kirik, Deniz and Annett, Lucy E. and Burger, Corinna and Muzyczka, Nicholas and Mandel, Ronald J. and Björklund, Anders},
  issn         = {1091-6490},
  language     = {eng},
  number       = {5},
  pages        = {2884--2889},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Nigrostriatal {alpha}-synucleinopathy induced by viral vector-mediated overexpression of human {alpha}-synuclein: A new primate model of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1073/pnas.0536383100},
  volume       = {100},
  year         = {2003},
}