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Human Molecular Genetics Advance Access originally published online on April 1, 2008
Human Molecular Genetics 2008 17(14):2071-2083; doi:10.1093/hmg/ddn106
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease

Sandro Alves1,2,7, Etienne Régulier4,{dagger}, Isabel Nascimento-Ferreira1,2, Raymonde Hassig7,8, Noelle Dufour7,8, Arnulf Koeppen5, Ana Luísa Carvalho1,3, Sérgio Simões1,2, Maria C. Pedroso de Lima1,3, Emmanuel Brouillet7,8, Veronica Colomer Gould6, Nicole Déglon7,8 and Luís Pereira de Almeida1,2,*

1 Center for Neurosciences and Cell Biology 2 Faculty of Pharmacy 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, NY, USA 6 Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MA, USA 7 CEA, Institute of Biomedical Imaging (I2BM) and Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France 8 CNRS, URA2210, Orsay, France

* To whom correspondence should be addressed at: Center for Neurosciences and Cell Biology and Faculty of Pharmacy, University of Coimbra, R. Norte, 3000-295 Coimbra, Portugal. Tel: +351 966337482; Fax: +351 239827126; Email: luispa{at}ci.uc.pt or lpereiradealmeida{at}gmail.com

Received February 5, 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 (LV), 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. LV encoding mutant or wild-type human ataxin-3 was 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; {alpha}-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 {alpha}-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD 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.

{dagger} Present address: Novartis, Target and Lead Discovery Unit, Basel, Switzerland.


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