Neuroprotective effects of inositol 1,4,5-trisphosphate receptor C-terminal fragment in a Huntington's disease mouse model

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 (InsP ₃R1), 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 InsP ₃R1 is a potential therapeutic target for HD. Our data also support potential use of IC10 peptide as a novel HD therapeutic agent.