期刊
JOURNAL OF NEUROSCIENCE
卷 28, 期 48, 页码 12713-12724出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3909-08.2008
关键词
calcium signaling; neurodegeneration; ataxin-3; spinocerebellar ataxia type 3; SCA3; Machado-Joseph disease; MJD1; transgenic mouse; stereology; dantrolene
资金
- The McKnight Neuroscience of Brain Disorders Award
- Robert A. Welch Foundation
- National Ataxia Foundation
- Ataxia MJD Research Project
- National Institute of Neurological Disorders and Stroke (NINDS) [R01NS38082, R01NS056224]
- National Institutes of Health (NIH) [F31 AG031692, U24NS05060]
- Ataxia UK and Ataxia MJD Research Project
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [17025044]
- University of California
- Grants-in-Aid for Scientific Research [17025044] Funding Source: KAKEN
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(3)R1), an intracellular calcium (Ca2+) release channel. In electrophysiological and Ca2+ imaging experiments, we show that InsP3R1 was sensitized to activation by InsP(3) in the presence of mutant ATX3(exp). 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.
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