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Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum

Régulier, Etienne ; Trottier, Yvon ; Perrin, Valérie ; Aebischer, Patrick ; Déglon, Nicole

In: Human Molecular Genetics, 2003, vol. 12, no. 21, p. 2827-2836

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    Titre
    • Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum
    Auteur
    • Régulier, Etienne. Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, EPFL, Lausanne, Switzerland and
    • Trottier, Yvon. Institut de Génétique et Biologie Cellulaire et Moléculaire, CNRS/INSERM/ULP, Illkirch, France
    • Perrin, Valérie. Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, EPFL, Lausanne, Switzerland and
    • Aebischer, Patrick. Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, EPFL, Lausanne, Switzerland and
    • Déglon, Nicole. Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, EPFL, Lausanne, Switzerland and
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Human Molecular Genetics, 2003, vol. 12, no. 21, p. 2827-2836. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:295774
    Summary
    The ability to overexpress full-length huntingtin or large fragments represents an important challenge to mimic Huntington's pathology and reproduce all stages of the disease in a time frame compatible with rodent life span. In the present study, tetracycline-regulated lentiviral vectors leading to high expression levels were used to accelerate the pathological process. Rats were simultaneously injected with vectors coding for the transactivator and wild type (WT) or mutated huntingtin (TRE-853-19Q/82Q) in the left and right striatum, respectively, and analyzed in the ‘on' and ‘off' conditions. Overexpression of TRE-853-19Q protein or residual expression of TRE-853-82Q in ‘off' condition did not cause any significant neuronal pathology. Overexpressed TRE-853-82Q protein led to proteolytic release of N-terminal htt fragments, nuclear aggregation, and a striatal dysfunction as revealed by decrease of DARPP-32 staining but absence of NeuN down-regulation. The differential effect on the DARPP-32/NeuN neuronal staining was observed as early as 1 month after injection and maintained at 3 months. In contrast, expression of a shorter htt form (htt171-82Q) did not require processing prior formation of nuclear aggregates and caused decrease of both DARPP-32 and NeuN neuronal markers at one month post-injection suggesting that polyQ pathology may be dependent on protein context. Finally, the reversibility of the pathology was assessed. Huntingtin expression was turn ‘on' for 1 month and then shut ‘off' for 2 months. Recovery of DARPP-32 immunoreactivity and clearance of huntingtin aggregates were observed in animals treated with doxycycline. These results suggest that a tetracycline-regulated system may be particularly attractive to model Huntington's disease and induce early and reversible striatal neuropathology in vivo