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J. Biol. Chem., Vol. 280, Issue 23, 22021-22028, June 10, 2005

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Phosphorylation of Arfaptin 2 at Ser²⁶⁰ by Akt Inhibits PolyQ-huntingtin-induced Toxicity by Rescuing Proteasome Impairment^*

Hélène Rangone, Raúl Pardo¶, Emilie Colin||, Jean-Antoine Girault**, Frédéric Saudou, and Sandrine Humbert

From the UMR 146 CNRS/Institut Curie, Centre Universitaire, 91405 Orsay Cedex, France and ^**INSERM/Université Pierre Marie Curie U536, Institut du Fer à Moulin, 75005 Paris, France

Huntington disease (HD) is caused by an abnormal expanded polyglutamine repeat in the huntingtin protein. Insulin-like growth factor-1 is of particular interest in HD because it strongly inhibits polyQ-huntingtin-induced neurotoxicity. This neuroprotective effect involves the phosphorylation of huntingtin at Ser⁴²¹ by the prosurvival kinase Akt (Humbert, S., Bryson, E. A., Cordelières, F. P., Connors, N. C., Datta, S. R., Finkbeiner, S., Greenberg, M. E., and Saudou, F. (2002) Dev. Cell 2, 831–837). Here, we report that Akt inhibits polyQ-huntingtin-induced toxicity in the absence of phosphorylation of huntingtin at Ser⁴²¹, suggesting that Akt also acts on other downstream effector(s) to prevent neuronal death in HD. We show that this survival effect involves the ADP-ribosylation factor-interacting protein arfaptin 2, the levels of which are increased in HD patients. Akt phosphorylated arfaptin 2 at Ser²⁶⁰. Lack of phosphorylation of arfaptin 2 at this site substantially modified its subcellular distribution and increased neuronal death and intranuclear inclusions caused by polyQ-huntingtin. In contrast, arfaptin 2 had a neuroprotective effect on striatal neurons when phosphorylated by Akt. This effect is mediated through the proteasome, as phosphorylated arfaptin 2 inhibited the blockade of the proteasome induced by polyQ-huntingtin. This study points out a new mechanism by which Akt promotes neuroprotection in HD, emphasizing the potential therapeutic interest of this pathway in the disease.

Received for publication, July 6, 2004 , and in revised form, February 28, 2005.

^* This work was supported in part by Association pour la Recherche sur le Cancer Grant 4807, Fondation pour la Recherche Médicale, Fondation Banque Nationale de Paris Paribas, European Communities Concerted Action Early Pathogenic Markers of Slow Neurogenerative Diseases Grant QLK6-CT-2000-0384, and the Provital/P. Chevalier and Hereditary Disease Foundation Cure Huntington Disease Initiative (to F. S.). The Harvard Brain Tissue Resource Center was supported in part by United States Public Health Service Grant MH/NS 31862. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Bourse de Doctorat pour Ingénieur-CNRS fellowship and a Fondation pour la Recherche Médicale doctoral fellowship.

^¶ Supported by a Fondation pour la Recherche Médicale postdoctoral fellowship.

^|| Supported by a doctoral fellowship from the French Research Ministry.

Recipient of a European Molecular Biology Organization young investigator award and an INSERM/Assistance Publique-Hôpitaux de Paris Investigator. To whom correspondence may be addressed. Tel.: 33-1-6986-3069; Fax: 33-1-6907-45-25; E-mail: frederic.saudou{at}curie.u-psud.fr. INSERM Investigator. To whom correspondence may be addressed: UMR 146 CNRS/Institut Curie, Bldg. 110, Centre Universitaire, 91405 Orsay Cedex, France. Tel.: 33-1-6986-3069; Fax: 33-1-6907-45-25; E-mail: sandrine.humbert{at}curie.u-psud.fr.

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