期刊
NEUROCHEMICAL RESEARCH
卷 36, 期 7, 页码 1186-1197出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-010-0393-y
关键词
Calcium signaling; Huntingtin; Neurodegeneration; Polyglutamine expansion; Inositol 1,4,5-trisphosphate; Ataxin-2; Ataxin-3; Spinocerebellar ataxias; Transgenic mice; NMDA receptor; Apoptosis; Mitochondria; Memantine
资金
- McKnight Neuroscience of Brain Disorders Award
- CHDI
- Hereditary Disease Foundation
- National Organization for Rare Disorders
- National Ataxia Foundation
- Ataxia MJD Research Project
- National Institutes of Health [R01NS38082, R01NS056224]
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 (IP(3)R1), an intracellular Ca2+ release channel. Moreover, we found that association of mutant huntingtin or ataxins with IP(3)R1 causes sensitization of IP(3)R1 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 SCA1, 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据