Abstract
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 (Ca(2+)) release channel. In electrophysiological and Ca(2+) imaging experiments, we show that InsP(3)R1 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 Ca(2+) signaling, improved their motor performance and prevented neuronal cell loss in pontine nuclei and substantia nigra regions. Our results indicate that deranged Ca(2+) signaling may play an important role in SCA3 pathology and that Ca(2+) signaling stabilizers such as dantrolene may be considered as potential therapeutic drugs for treatment of SCA3 patients.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Animals, Genetically Modified
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Ataxin-3
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Brain / drug effects
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Brain / metabolism*
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Brain / physiopathology
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Calcium Signaling / drug effects
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Calcium Signaling / genetics*
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Cells, Cultured
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Dantrolene / pharmacology*
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Dantrolene / therapeutic use
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Disease Models, Animal
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Genetic Predisposition to Disease / genetics
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Humans
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Inositol 1,4,5-Trisphosphate Receptors / metabolism*
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Machado-Joseph Disease / drug therapy
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Machado-Joseph Disease / metabolism*
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Machado-Joseph Disease / physiopathology
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Mice
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Mice, Inbred C57BL
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Muscle Relaxants, Central / pharmacology
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Muscle Relaxants, Central / therapeutic use
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Mutation / genetics
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Nerve Degeneration / drug therapy
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Nerve Degeneration / physiopathology
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Nerve Degeneration / prevention & control
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Nuclear Proteins / genetics*
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Pons / drug effects
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Pons / pathology
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Pons / physiopathology
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Rats
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Recovery of Function / drug effects
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Recovery of Function / physiology
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Substantia Nigra / drug effects
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Substantia Nigra / pathology
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Substantia Nigra / physiopathology
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Transcription Factors / genetics*
Substances
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Inositol 1,4,5-Trisphosphate Receptors
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Muscle Relaxants, Central
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Nuclear Proteins
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Transcription Factors
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Ataxin-3
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Atxn3 protein, mouse
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Dantrolene