Role of Inositol 1,4,5-Trishosphate Receptors in Pathogenesis of Huntington’s Disease and Spinocerebellar Ataxias
- 6 January 2011
- journal article
- review article
- Published by Springer Science and Business Media LLC in Neurochemical Research
- Vol. 36 (7), 1186-1197
- https://doi.org/10.1007/s11064-010-0393-y
Abstract
Huntington’s disease (HD) and spinocerebellar ataxias (SCAs) are autosomal-dominant neurodegenerative disorders. HD is caused by polyglutamine (polyQ) expansion in the amino-terminal region of a protein huntingtin (Htt) and primarily affects medium spiny striatal neurons (MSN). Many SCAs are caused by polyQ-expansion in ataxin proteins and primarily affect cerebellar Purkinje cells. The reasons for neuronal dysfunction and death in HD and SCAs remain poorly understood and no cure is available for the patients. Our laboratory discovered that mutant huntingtin, ataxin-2 and ataxin-3 proteins specifically bind to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1), an intracellular Ca2+ release channel. Moreover, we found that association of mutant huntingtin or ataxins with IP3R1 causes sensitization of IP3R1 to activation by IP3 in planar lipid bilayers and in neuronal cells. These results suggested that deranged neuronal Ca2+ signaling might play an important role in pathogenesis of HD, SCA2 and SCA3. In support of this idea, we demonstrated a connection between abnormal Ca2+ signaling and neuronal cell death in experiments with HD, SCA2 and SCA3 transgenic mouse models. Additional data in the literature indicate that abnormal neuronal Ca2+ signaling may also play an important role in pathogenesis of SCAl, SCA5, SCA6, SCA14 and SCA15/16. Based on these results I propose that IP3R and other Ca2+ signaling proteins should be considered as potential therapeutic targets for treatment of HD and SCAs.Keywords
This publication has 131 references indexed in Scilit:
- Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other AtaxiasThe Cerebellum, 2010
- Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtinNature Medicine, 2009
- Secondary Structure of Huntingtin Amino-Terminal RegionStructure, 2009
- Emerging pathogenic pathways in the spinocerebellar ataxiasCurrent Opinion in Genetics & Development, 2009
- Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAsNature Biotechnology, 2009
- Calcium signaling and neurodegenerative diseasesTrends in Molecular Medicine, 2009
- Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca V 2.1 channelsProceedings of the National Academy of Sciences of the United States of America, 2008
- Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington's diseaseNeurobiology of Disease, 2008
- Synaptic NMDA receptor activity boosts intrinsic antioxidant defensesNature Neuroscience, 2008
- RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxiaNature Medicine, 2004