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Vol. 17, Issue 4, 1652-1663, April 2006
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* URA CEA-CNRS 2210, Service Hospitalier Frédéric Joliot, MIRCen Program, Département de Recherches Médicales, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique (CEA), 91401 Orsay Cedex, France;
Swiss Federal Institute of Technology Lausanne, Institute of Neurosciences, EPFL, CH 1015 Lausanne, Switzerland;
Service de Biochimie et de Génétique Moléculaire, Département de Biologie Joliot-Curie, CEA Saclay, 91191 Gif-sur-Yvette Cedex, France;
INSERM U421, Faculté de Médecine, Créteil 94010 Cedex, France;
|| UMR 146, Centre National de la Recherche Scientifique/Institut Curie, Centre Universitaire, 91405 Orsay Cedex, France; and
¶ INSERM U679 (formerly U289), Neurologie et Thérapeutique Expérimentale, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France
Submitted July 7, 2005;
Accepted January 23, 2006
Monitoring Editor: Donald Newmeyer
Alterations of mitochondrial function may play a central role in neuronal death in Huntington's disease (HD). However, the molecular mechanisms underlying such functional deficits of mitochondria are not elucidated yet. We herein showed that the expression of two important constituents of mitochondrial complex II, the 30-kDa iron-sulfur (Ip) subunit and the 70-kDa FAD (Fp) subunit, was preferentially decreased in the striatum of HD patients compared with controls. We also examined several mitochondrial proteins in striatal neurons that were infected with lentiviral vectors coding for the N-terminus part of huntingtin (Htt) with either a pathological (Htt171-82Q) or physiological (Htt171-19Q) polyglutamine tract. Compared with Htt171-19Q, expression of Htt171-82Q preferentially decreased the levels of Ip and Fp subunits and affected the dehydrogenase activity of the complex. The Htt171-82Q–induced preferential loss of complex II was not associated with a decrease in mRNA levels, suggesting the involvement of a posttranscriptional mechanism. Importantly, the overexpression of either Ip or Fp subunit restored complex II levels and blocked mitochondrial dysfunction and striatal cell death induced by Htt171-82Q in striatal neurons. The present results strongly suggest that complex II defects in HD may be instrumental in striatal cell death.
Abbreviations used: HD, Huntington's disease; Htt, huntingtin; IRE, iron responsive element; mPTP, mitochondrial permeability transition pore; 3NP, 3-nitropropionic acid; polyQ, polyglutamine; SDH, succinate dehydrogenase; UTR, untranslated region.
Address correspondence to: Emmanuel Brouillet (brouille{at}shfj.cea.fr).
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