Huntingtin phosphorylation and signaling pathways that regulate toxicity in Huntington's disease

Despite an intensive research on the protein huntingtin that causes Huntington's disease, little is known about the dystregulation of signal transduction pathways and their role in the pathological process. PolyQ expansion in huntingtin causes the activation of various pathways that may participate in cell death. Of particular interest is the role of the mitogen activated protein kinases. In addition, modification of huntingtin by phosphorylation might also play an important role in the disease by modulating the toxicity of mutant polyQ-huntingtin. For instance. phosphorylation of polyQ-huntingtin at serine 421 is induced by the pro-survival pathway insulin growth factor 1/Akt leading to a decreased polyQ-huntingtin-induced cell death. Studying such neuronal survival and death pathways and their components in HD will certainly lead to a better knowledge of huntingtin function/dysfunction in disease. (C) 2003 Elsevier B.V. All rights reserved.