normal aging modulates the neurotoxicity of mutant huntingtin正常衰老调节突变杭丁顿蛋白的神经毒性.pdfVIP

Normal Aging Modulates the Neurotoxicity of Mutant Huntingtin 1,2 1,2 1,2 1,2 1,2 ¨ 1,2 Elsa Diguet , Fanny Petit , Carole Escartin , Karine Cambon , Nicolas Bizat , Noelle Dufour , 1,2 ´ 1,2 1,2 Philippe Hantraye , Nicole Deglon , Emmanuel Brouillet * ` ´ 1 Commissariat a l’Energie Atomique (CEA), Institut d’Imagerie Biomedicale (I2BM), Molecular Imaging Research Center (MIRCen), Orsay, France, 2 Centre National de la ´ ´ Recherche Scientifique (CNRS), Unite de Recherche Associee CEA-CNRS 2210, Orsay, France Abstract Aging likely plays a role in neurodegenerative disorders. In Huntington’s disease (HD), a disorder caused by an abnormal expansion of a polyglutamine tract in the protein huntingtin (Htt), the role of aging is unclear. For a given tract length, the probability of disease onset increases with age. There are mainly two hypotheses that could explain adult onset in HD: Either mutant Htt progressively produces cumulative defects over time or ‘‘normal’’ aging renders neurons more vulnerable to mutant Htt toxicity. In the present study, we directly explored whether aging affected the toxicity of mutant Htt in vivo. We studied the impact of aging on the effects produced by overexpression of an N-terminal fragment of mutant Htt, of wild-type Htt or of a b-Galactosidase (b-Gal) reporter gene in the rat striatum. Stereotaxic injections of lentiviral vectors were performed simultaneously in young (3 week) and old (15 month)