Aberrant IP 3 receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29

Significance Spinocerebellar ataxias (SCAs) are neurological disorders caused by cerebellar dysfunction. Missense mutations in inositol 1,4,5-trisphosphate (IP 3 ) receptor type 1 (IP 3 R1), an IP 3 -gated intracellular Ca 2+ channel, are associated with infantile-onset nonprogressive SCA. However, the molecular mechanisms of how mutations in IP 3 R1 cause SCA remain unclear. We demonstrated that pathological mutations in IP 3 R1 disrupt IP 3 R1 channel activity either by reducing IP 3 -binding affinity or hindering channel gating elicited by IP 3 binding. Furthermore, disease-causing mutations in IP 3 R1 or carbonic anhydrase-related protein VIII (CA8), an IP 3 R1-regulating protein abundantly expressed in cerebellar neurons, abrogated the IP 3 R1–CA8 interaction and CA8-mediated regulation of IP 3 R1. These results suggest that aberrant calcium homeostasis in cerebellar neurons caused by dysfunctions of IP 3 R1 are responsible for SCA pathogenesis.