title: Akt is altered in an animal model of Huntington's disease and in patients.
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.
authors.affiliation: UMR 146 CNRS/Institut Curie, Bldg. 110, Centre Universitaire, Orsay, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Colin
authors.forename: Etienne
authors.initials: E
authors.lastname: Régulier
authors.forename: Valérie
authors.initials: V
authors.lastname: Perrin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
mesh_terms: D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006868:Hydrolysis; D008214:Lymphocytes / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases