Huntingtin Phosphorylation

Science's STKE  18 Jun 2002:
Vol. 2002, Issue 137, pp. tw215
DOI: 10.1126/stke.2002.137.tw215

Huntington's disease (HD) is characterized by progressive brain neurodegeneration, often leading to dementia. A mutation in the huntingtin protein and nuclear accumulation of the mutant are associated with the pathology of HD, but it is not yet clear how the mutant protein induces the death of neurons. Growth factors that promote cell survival are attractive therapeutic agents for HD; Humbert et al. report that insulin-like growth factor 1 (IGF-1) shows just such neuroprotective potential. IGF-1 promotes cell survival through activation of the serine-threonine kinase Akt. The study shows that a specific serine residue in huntingtin is phosphorylated by Akt both in vitro and in neuronal cells in response to IGF-1. Furthermore, this IGF-1-induced modification blocked the formation of nuclear inclusions and neuronal apoptosis. Brain samples from HD patients also showed decreased amounts of Akt. Phosphorylation by Akt may alter HD interactions with proteins that promote apoptosis and, hence, abrogate its toxicity.

S. Humbert, E. A. Bryson, F. P. Cordelieres, N. C. Connors, S. R. Datta, S. Finkbeiner, M. E. Greenberg, F. Saudou, The IGF-1 pathway is neuroprotective in Huntingon's disease and involves huntingtin phosphorylation by Akt. Dev. Cell 2, 831-837 (2002). [Online Journal]