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The Journal of Neuroscience, July 22, 2009, 29(29):9148-9162; doi:10.1523/JNEUROSCI.0660-09.2009

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Neurobiology of Disease
Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 2

Jing Liu,¹ Tie-Shan Tang,¹ Huiping Tu,¹ Omar Nelson,¹ Emily Herndon,² Duong P. Huynh,³ Stefan M. Pulst,^3,4 and Ilya Bezprozvanny¹

¹Departments of Physiology and ²Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, and ³Department of Neurology and ⁴Utah Brain Institute, University of Utah, Salt Lake City, Utah 84112

Correspondence should be addressed to Dr. Ilya Bezprozvanny, Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email: ilya.bezprozvanny{at}UTSouthwestern.edu

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited, neurodegenerative disease caused by an expansion of polyglutamine tracts in the cytosolic protein ataxin-2 (Atx2). Cerebellar Purkinje cells (PCs) are predominantly affected in SCA2. The cause of PC degeneration in SCA2 is unknown. Here we demonstrate that mutant Atx2–58Q, but not wild-type (WT) Atx2–22Q, specifically associates with the cytosolic C-terminal region of type 1 inositol 1,4,5-trisphosphate receptor (InsP₃R1), an intracellular calcium (Ca²⁺) release channel. Association with Atx2–58Q increased the sensitivity of InsP₃R1 to activation by InsP₃ in planar lipid bilayer reconstitution experiments. To validate physiological significance of these findings, we performed a series of experiments with an SCA2–58Q transgenic mouse model that expresses human full-length Atx2–58Q protein under the control of a PC-specific promoter. In Ca²⁺ imaging experiments, we demonstrated that stimulation with 3,5-dihydroxyphenylglycine (DHPG) resulted in higher Ca²⁺ responses in 58Q PC cultures than in WT PC cultures. DHPG-induced Ca²⁺ responses in 58Q PC cultures were blocked by the addition of ryanodine, an inhibitor of the ryanodine receptor (RyanR). We further demonstrated that application of glutamate induced more pronounced cell death in 58Q PC cultures than in WT PC cultures. Glutamate-induced cell death of 58Q PC cultures was attenuated by dantrolene, a clinically relevant RyanR inhibitor and Ca²⁺ stabilizer. In whole animal experiments, we demonstrated that long-term feeding of SCA1–58Q mice with dantrolene alleviated age-dependent motor deficits (quantified in beam-walk and rotarod assays) and reduced PC loss observed in untreated SCA2–58Q mice by 12 months of age (quantified by stereology). Results of our studies indicate that disturbed neuronal Ca²⁺ signaling may play an important role in SCA2 pathology and also suggest that the RyanR constitutes a potential therapeutic target for treatment of SCA2 patients.

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Received Feb. 4, 2009; revised March 18, 2009; accepted June 7, 2009.

Correspondence should be addressed to Dr. Ilya Bezprozvanny, Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email: ilya.bezprozvanny{at}UTSouthwestern.edu

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