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Akt is altered in an animal model of Huntington's disease and in patients

2005; Wiley; Volume: 21; Issue: 6 Linguagem: Inglês

10.1111/j.1460-9568.2005.03985.x

1460-9568

Emilie Colin, Etienne Régulier, Valérie Perrin, Alexandra Dürr, Alexis Brice, Patrick Aebischer, Nicole Déglon, Sandrine Humbert, Frédéric Saudou,

Mitochondrial Function and Pathology

Abstract The insulin‐like growth factor I (IGF‐1)/Akt pathway plays a crucial role in Huntington's disease by phosphorylating the causative protein, polyQ‐huntingtin, and abolishing its toxic properties [ Humbert et al . (2002) Dev. Cell , 2, 831–837; Rangone et al . (2004) Eur. J. Neurosci ., 19, 273–279]. Therefore, dysregulation of this pathway may be essential for disease progression. In the present report, we thus aimed to analyse the status of Akt in brain or in peripheral tissues in Huntington's disease. Using a genetic model of Huntington's disease in rat that reproduces neuronal dysfunction and death, we show a progressive alteration of Akt during neuronal dysfunction and prior neurodegeneration. By analysing a limited number of lymphoblasts and lymphocytes, we detected modifications of Akt in Huntington's disease patients confirming a dysregulation of Akt in the disease process. Finally, we demonstrate that during late stages of the disease, Akt is cleaved into an inactive form by caspase‐3. These observations demonstrate a progressive but marked alteration of this pro‐survival pathway in Huntington's disease, and further implicate it as a key transduction pathway regulating the toxicity of huntingtin.