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Significance Spinocerebellar ataxias (SCAs) are neurological disorders caused by cerebellar dysfunction. Missense mutations in inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), an IP3 -gated intracellular Ca2+ channel, are associated with infantile-onset nonprogressive SCA. However, the molecular mechanisms of how mutations in IP3 R1 cause SCA remain unclear. We demonstrated that pathological mutations in IP3 R1 disrupt IP3 R1 channel activity either by reducing IP3 -binding affinity or hindering channel gating elicited by IP3 binding. Furthermore, disease-causing mutations in IP3 R1 or carbonic anhydrase-related protein VIII (CA8), an IP3 R1-regulating protein abundantly expressed in cerebellar neurons, abrogated the IP3 R1–CA8 interaction and CA8-mediated regulation of IP3 R1. These results suggest that aberrant calcium homeostasis in cerebellar neurons caused by dysfunctions of IP3 R1 are responsible for SCA pathogenesis.

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

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