Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington's disease

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder that has no cure. HD primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Htt(exp) and MSN neurodegeneration remains elusive. My laboratory discovered that mutant Htt(exp) protein specifically binds to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1), an intracellular Ca2+ release channel. Moreover, we found that Htt(exp) association with InsP3R1 causes sensitization of InsP3R1 to activation by InsP3 in planar lipid bilayers and in primary MSN. Mutant Htt(exp) has also been shown to activate Ca2(+)-permeable NR2B-containing NMDA receptors. All these results suggested that deranged neuronal Ca2+ signaling may play an important role in pathogenesis of HD. In support of this idea, we demonstrated a connection between abnormal Ca2+ signaling and apoptosis of MSN cultured from YAC128 HD mouse model. These results indicate that InsP3R and other Ca2+ signaling proteins should be considered as potential therapeutic targets for treatment of HD.