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

Tie Shan Tang, Caixia Guo, Hongyu Wang, Xi Chen, Ilya Bezprozvanny

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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 (Httexp) 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 Httexp 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- Httexp 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.

Original languageEnglish (US)
Pages (from-to)1257-1266
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number5
DOIs
StatePublished - Feb 4 2009

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Inositol 1,4,5-Trisphosphate Receptors
Huntington Disease
Neuroprotective Agents
Corpus Striatum
Neurons
Dependovirus
Mutant Proteins
Neurodegenerative Diseases
Transgenic Mice
Tail
Glutamic Acid
Apoptosis
Pathology
Viruses
Peptides
Injections
Therapeutics
Infection

Keywords

  • Calcium signaling
  • Huntington's disease
  • InsPR
  • Neurodegeneration
  • Recombinant adeno-associated virus (AAV)
  • Stereology
  • Transgenic mouse

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Neuroprotective effects of inositol 1,4,5-trisphosphate receptor C-terminal fragment in a Huntington's disease mouse model. / Tang, Tie Shan; Guo, Caixia; Wang, Hongyu; Chen, Xi; Bezprozvanny, Ilya.

In: Journal of Neuroscience, Vol. 29, No. 5, 04.02.2009, p. 1257-1266.

Research output: Contribution to journalArticle

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