Human Molecular Genetics Advance Access published online on April 1, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn106
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Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease
1 Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal 2 Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal 3 Faculty of Sciences, University of Coimbra, Coimbra, Portugal 4 Ecole Polytechnique Fédérale de Lausanne (EPFL), Brain Mind Institute, Lausanne, Switzerland 5 VA Medical Center and Albany Medical College, Albany, N.Y.; USA 6 Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 7 CEA, Institute of Biomedical Imaging (I2BM) and Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France 8 CNRS, URA2210, Orsay, France
* Correspondence: Luis Pereira de Almeida Center for Neurosciences & Cell Biology and Faculty of Pharmacy, University of Coimbra, R. Norte, 3000-295 Coimbra, Portugal Phone: 351 96 633 74 82 Fax: 351 239 827126 E-mail: luispa{at}ci.uc.pt lpereiradealmeida{at}gmail.com
Received February 5, 2008; Revised March 29, 2008; Accepted March 29, 2008
Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors, to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD.
Lentiviral vectors encoding mutant or wild-type human ataxin-3 were injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue.
In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; 
-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and -synuclein.
This study demonstrates the use of lentiviral vectors encoding mutant ataxin-3 to produce a model of Machado-Joseph disease and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies.
Present address: Novartis, Target & Lead Discovery Unit, Basel, Switzerland