@article {Chen12713, author = {Xi Chen and Tie-Shan Tang and Huiping Tu and Omar Nelson and Mark Pook and Robert Hammer and Nobuyuki Nukina and Ilya Bezprozvanny}, title = {Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 3}, volume = {28}, number = {48}, pages = {12713--12724}, year = {2008}, doi = {10.1523/JNEUROSCI.3909-08.2008}, publisher = {Society for Neuroscience}, abstract = {Spinocerebellar ataxia type 3 (SCA3), also known as Machado{\textendash}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 ATX3exp specifically associated with the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1), 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 Ca2+ 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.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/28/48/12713}, eprint = {https://www.jneurosci.org/content/28/48/12713.full.pdf}, journal = {Journal of Neuroscience} }