Developmental Cell 2: 831-837 (2002)

The IGF-1/Akt Pathway Is Neuroprotective in Huntington's Disease and Involves Huntingtin Phosphorylation by Akt

Sandrine Humbert, Elzbieta A. Bryson, Fabrice P. Cordelieres, Nathan C. Connors, Sandeep R. Datta, Steven Finkbeiner, Michael E. Greenberg, and Frederic Saudou

UMR 146 CNRS/Institut Curie Centre Universitaire 91405 Orsay Cedex France
Division of Neuroscience Children's Hospital and Department of Neurobiology Harvard Medical School Boston, Massachusetts 02115, USA
Gladstone Institute for Neurological Disorders University of California, San Francisco San Francisco, California 94141, USA

In the search for neuroprotective factors in Hunting- tonŐs disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglu tamine stretch. The IGF-1/Akt pathway has a dual ef fect on huntingtin-induced toxicity, since activation of this pathway also results in a decrease in the formation of intranuclear inclusions of mutant huntingtin. We demonstrate that huntingtin is a substrate of Akt and that phosphorylation of huntingtin by Akt is crucial to mediate the neuroprotective effects of IGF-1. Finally, we show that Akt is altered in HuntingtonŐs disease patients. Taken together, these results support a po tential role of the Akt pathway in HuntingtonŐs disease.