Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3

Xi Chen, Tie Shan Tang, Huiping Tu, Omar Nelson, Mark Pook, Robert E Hammer, Nobuyuki Nukina, Ilya Bezprozvanny

Research output: Contribution to journalArticlepeer-review

184 Scopus citations


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 ATX3exp 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.

Original languageEnglish (US)
Pages (from-to)12713-12724
Number of pages12
JournalJournal of Neuroscience
Issue number48
StatePublished - Nov 26 2008


  • Ataxin-3
  • Calcium signaling
  • Dantrolene
  • MJD1
  • Machado-Joseph disease
  • Neurodegeneration
  • SCA3
  • Spinocerebellar ataxia type 3
  • Stereology
  • Transgenic mouse

ASJC Scopus subject areas

  • Neuroscience(all)


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