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The Journal of Neuroscience, November 26, 2008, 28(48):12713-12724; doi:10.1523/JNEUROSCI.3909-08.2008

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Neurobiology of Disease
Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 3

Xi Chen,¹ Tie-Shan Tang,¹ Huiping Tu,¹ Omar Nelson,¹ Mark Pook,³ Robert Hammer,² Nobuyuki Nukina,⁴ and Ilya Bezprozvanny¹

Departments of ¹Physiology and ²Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, ³School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex UB8 3PH, United Kingdom, and ⁴Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan

Correspondence should be addressed to Dr. Ilya Bezprozvanny at the above address. Email: ilya.bezprozvanny{at}utsouthwestern.edu

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 (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 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.

Key words: calcium signaling; neurodegeneration; ataxin-3; spinocerebellar ataxia type 3; SCA3; Machado–Joseph disease; MJD1; transgenic mouse; stereology; dantrolene

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Received Aug. 15, 2008; accepted Oct. 7, 2008.

Correspondence should be addressed to Dr. Ilya Bezprozvanny at the above address. Email: ilya.bezprozvanny{at}utsouthwestern.edu

This article has been cited by other articles:

				J. Liu, T.-S. Tang, H. Tu, O. Nelson, E. Herndon, D. P. Huynh, S. M. Pulst, and I. Bezprozvanny Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 2 J. Neurosci., July 22, 2009; 29(29): 9148 - 9162. [Abstract] [Full Text] [PDF]

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