Inositol 1,4,5-tripshosphate receptor, calcium signaling, and polyglutamine expansion disorders.

Huntington’s disease (HD), spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are autosomal-dominant neurodegenerative disorders. HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt) and primarily affects medium spiny striatal neurons (MSN). SCA2 is caused by a polyQ expansion in the amino-terminal region of a cytosolic protein ataxin-2 (Atxn2) and primarily affects cerebellar Purkinje neurons. SCA3 is caused by a polyQ expansion in the carboxy-terminal portion of a cytosolic protein ataxin-3 (Atxn3) and primarily affects dentate and pontine nuclei and substantia nigra. The reasons for neuronal dysfunction and death in HD, SCA2 and SCA3 remain poorly understood and no cure is available for the patients. My laboratory discovered that mutant Huntingtin, ataxin-2 and ataxin-3 proteins specifically binds to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (IPR1), an intracellular Ca release channel. Moreover, we found that association with IPR1 causes sensitization of IPR1 to activation by IP in planar lipid bilayers and in neuronal cells. These results suggested that deranged neuronal Ca signaling might play an important role in pathogenesis of HD, SCA2 and SCA3. In support of this idea, we demonstrated a connection between abnormal Ca signaling and neuronal cell death in experimnts with HD, SCA2 and SCA3 transgenic mouse models. Based on these results I propose that IPR and other Ca signaling proteins should be considered as potential therapeutic targets for treatment of HD, SCA2 and SCA3.