ORIGINAL PAPER Overexpression of Mutant Ataxin-3 in Mouse Cerebellum Induces Ataxia and Cerebellar Neuropathology Clévio Nóbrega & Isabel Nascimento-Ferreira & Isabel Onofre & David Albuquerque & Mariana Conceição & Nicole Déglon & Luís Pereira de Almeida # Springer Science+Business Media New York 2012 Abstract Machado–Joseph disease (MJD), also known as spi- nocerebellar ataxia type 3 (SCA3), is a fatal, dominant neurode- generative disorder caused by the polyglutamine-expanded protein ataxin-3. Clinical manifestations include cerebellar ataxia and pyramidal signs culminating in severe neuronal degenera- tion. Currently, there is no therapy able to modify disease pro- gression. In the present study, we aimed at investigating one of the most severely affected brain regions in the disorder— the cerebellum—and the behavioral defects associated with the neuropathology in this region. For this purpose, we injected lentiviral vectors encoding full-length human mutant ataxin-3 in the mouse cerebellum of 3-week-old C57/BL6 mice. We show that circumscribed expression of human mutant ataxin-3 in the cerebellum mediates within a short time frame—6 weeks, the development of a behavioral phenotype including reduced motor coordination, wide-based ataxic gait, and hyperactivity. Furthermore, the expression of mutant ataxin-3 resulted in the accumulation of intranuclear inclusions, neuropathological ab- normalities, and neuronal death. These data show that lentiviral- based expression of mutant ataxin-3 in the mouse cerebellum induces localized neuropathology, which is sufficient to generate a behavioral ataxic phenotype. Moreover, this approach provides a physiologically relevant, cost-effective and time-effective ani- mal model to gain further insights into the pathogenesis of MJD and for the evaluation of experimental therapeutics of MJD. Keywords Ataxin-3 . Cerebellum . Machado–Joseph disease . Lentiviral vectors . Mouse model of disease . In vivo Introduction Polyglutamine (polyQ) repeat diseases are caused by the expansion of an unstable CAG repeat in the coding region of the respective disease gene [1], leading to an abnormally long polyQ tract, which causes dominant pathogenesis. Nine polyQ disorders have been described, including Hunting- ton’ s disease (HD), spinal–bulbar muscular atrophy, denta- torubral –pallidoluysian atrophy (DRPLA), and several spinocerebellar ataxias (SCA1–3, 6–7, 17) [1, 2]. Machado–Joseph disease (MJD), also called spinocerebel- lar ataxia type 3 (SCA3), is a dominantly inherited disorder of the central nervous system (CNS). MJD results from an ab- normal increased repetition of the trinucleotide CAG in the MJD-1 gene, translating into an expanded polyQ tract that Electronic supplementary material The online version of this article (doi:10.1007/s12311-012-0432-0) contains supplementary material, which is available to authorized users. Clévio Nóbrega and Isabel Nascimento-Ferreira contributed equally to this work. C. Nóbrega : I. Nascimento-Ferreira : I. Onofre : M. Conceição : L. P. de Almeida Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal I. Nascimento-Ferreira : I. Onofre : M. Conceição : L. P. de Almeida (*) Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal e-mail: luispa@ci.uc.pt L. P. de Almeida e-mail: luispa@cnc.uc.pt D. Albuquerque Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal I. Nascimento-Ferreira Molecular Imaging Research Center, CEA, Fontenay-aux-Roses, France N. Déglon Laboratory of Cellular and Molecular Neurotherapies, Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland Cerebellum DOI 10.1007/s12311-012-0432-0