Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 3

• Published in: The Journal of neuroscience Vol. 28; no. 48; pp. 12713 - 12724
• Main Authors: Chen, Xi, Tang, Tie-Shan, Tu, Huiping, Nelson, Omar, Pook, Mark, Hammer, Robert, Nukina, Nobuyuki, Bezprozvanny, Ilya
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 26.11.2008; Society for Neuroscience
• Subjects: Adult; Animals; Animals, Genetically Modified; Ataxin-3; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Calcium Signaling - drug effects; Calcium Signaling - genetics; Cells, Cultured; Dantrolene - pharmacology; Dantrolene - therapeutic use; Disease Models, Animal; Genetic Predisposition to Disease - genetics; Humans; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Machado-Joseph Disease - drug therapy; Machado-Joseph Disease - metabolism; Machado-Joseph Disease - physiopathology; Mice; Mice, Inbred C57BL; Muscle Relaxants, Central - pharmacology; Muscle Relaxants, Central - therapeutic use; Mutation - genetics; Nerve Degeneration - drug therapy; Nerve Degeneration - physiopathology; Nerve Degeneration - prevention & control; Nuclear Proteins - genetics; Pons - drug effects; Pons - pathology; Pons - physiopathology; Rats; Recovery of Function - drug effects; Recovery of Function - physiology; Substantia Nigra - drug effects; Substantia Nigra - pathology; Substantia Nigra - physiopathology; Transcription Factors - genetics
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3909-08.2008

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.