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The Journal of Neuroscience, February 4, 2009, 29(5):1257-1266; doi:10.1523/JNEUROSCI.4411-08.2009

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Neurobiology of Disease
Neuroprotective Effects of Inositol 1,4,5-Trisphosphate Receptor C-Terminal Fragment in a Huntington's Disease Mouse Model

Tie-Shan Tang,¹ Caixia Guo,² Hongyu Wang,¹ Xi Chen,¹ and Ilya Bezprozvanny¹

Departments of ¹Physiology and ²Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

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

Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disease caused by an expanded polyglutamine tract in huntingtin protein (Htt). Medium spiny striatal neurons (MSNs) are primarily affected in HD. Mutant huntingtin protein (Htt^exp) specifically binds to and activates type 1 inositol 1,4,5-trisphosphate receptor (InsP₃R1), an intracellular Ca²⁺ release channel. Htt^exp–InsP₃R1 association is mediated by a cytosolic C-terminal tail of InsP₃R1 (a 122-aa-long IC10 fragment). To evaluate an importance of Htt^exp association with InsP₃R1 for HD pathology, we generated lentiviral and adeno-associated viruses expressing GFP-IC10 fusion protein and performed a series of experiments with YAC128 HD transgenic mouse. Infection with Lenti-GFP-IC10 virus stabilized Ca²⁺ signaling in cultured YAC128 MSNs and protected YAC128 MSNs from glutamate-induced apoptosis. Intrastriatal injections of AAV1-GFP-IC10 significantly alleviated motor deficits and reduced MSN loss and shrinkage in YAC128 mice. Our results demonstrate an importance of InsP₃R1–Htt^exp association for HD pathogenesis and suggested that InsP₃R1 is a potential therapeutic target for HD. Our data also support potential use of IC10 peptide as a novel HD therapeutic agent.

Key words: calcium signaling; neurodegeneration; InsP₃R; recombinant adeno-associated virus (AAV); Huntington's disease; transgenic mouse; stereology

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Received Sept. 15, 2008; revised Oct. 23, 2008; accepted Dec. 20, 2008.

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

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