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The Journal of Neuroscience, February 1, 2006, 26(5):1635-1645; doi:10.1523/JNEUROSCI.3706-05.2006

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Neurobiology of Disease
Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

Raúl Pardo,¹ Emilie Colin,¹ Etienne Régulier,² Patrick Aebischer,² Nicole Déglon,³ Sandrine Humbert,¹ and Frédéric Saudou¹

¹Institut Curie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 146, 91405 Orsay, France, ²École Polytechnique Fédérale de Lausanne, Institute of Neurosciences, CH-1015 Lausanne, Switzerland, and ³Atomic Energy Commission, Department of Medical Research and ImaGene Program, 91400 Orsay, France

Correspondence should be addressed to either Sandrine Humbert or Frédéric Saudou, Institut Curie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 146, Building 110, Centre Universitaire, 91405 Orsay, France. Email: Sandrine.Humbert{at}curie.u-psud.fr or Frederic.Saudou{at}curie.u-psud.fr.

Huntington’s disease (HD) is caused by an abnormal expanded polyglutamine (polyQ) repeat in the huntingtin protein. Insulin-like growth factor-1 acting through the prosurvival kinase Akt mediates the phosphorylation of huntingtin at S421 and inhibits the toxicity of polyQ-expanded huntingtin in cell culture, suggesting that compounds enhancing phosphorylation are of therapeutic interest. However, it is not clear whether phosphorylation of S421 is crucial in vivo. Using a rat model of HD based on lentiviral-mediated expression of a polyQ-huntingtin fragment in the striatum, we demonstrate here that phosphorylation of S421 is neuroprotective in vivo. We next demonstrate that calcineurin (CaN), a calcium/calmodulin-regulated Ser/Thr protein phosphatase, dephosphorylates S421 in vitro and in cells. Inhibition of calcineurin activity, either by overexpression of the dominant-interfering form of CaN or by treatment with the specific inhibitor FK506, favors the phosphorylation of S421, restores the alteration in huntingtin S421 phosphorylation in HD neuronal cells, and prevents polyQ-mediated cell death of striatal neurons. Finally, we show that administration of FK506 to mice increases huntingtin S421 phosphorylation in brain. Collectively, these data highlight the importance of CaN in the modulation of S421 phosphorylation and suggest the potential use of CaN inhibition as a therapeutic approach to treat HD.

Key words: Huntington disease; polyglutamine; protein phosphatase 2B; lentiviruses; rat model; calcium; neuroprotection

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Received Sept. 1, 2005; revised Dec. 7, 2005; accepted Dec. 19, 2005.

Correspondence should be addressed to either Sandrine Humbert or Frédéric Saudou, Institut Curie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 146, Building 110, Centre Universitaire, 91405 Orsay, France. Email: Sandrine.Humbert{at}curie.u-psud.fr or Frederic.Saudou{at}curie.u-psud.fr.

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