Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in ataxin-3 (ATX3; MJD1) protein. In biochemical experiments, we demonstrate that mutant ATX3^exp specifically associated with the type 1 inositol 1,4,5-trisphosphate receptor (InsP ₃R1), an intracellular calcium (Ca²⁺) release channel. In electrophysiological and Ca²⁺ imaging experiments, we show that InsP₃R1 was sensitized to activation by InsP₃ in the presence of mutant ATX3exp. We found that feeding SCA3-YAC-84Q transgenic mice with dantrolene, a clinically relevant stabilizer of intracellular Ca ²⁺ signaling, improved their motor performance and prevented neuronal cell loss in pontine nuclei and substantia nigra regions. Our results indicate that deranged Ca²⁺ signaling may play an important role in SCA3 pathology and that Ca²⁺ signaling stabilizers such as dantrolene may be considered as potential therapeutic drugs for treatment of SCA3 patients.