Role of inositol 1,4,5-trishosphate receptors in pathogenesis of Huntington's disease and spinocerebellar ataxias

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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 IP 3R1 causes sensitization of IP3R1 to activation by IP 3 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.

Original languageEnglish (US)
Pages (from-to)1186-1197
Number of pages12
JournalNeurochemical Research
Volume36
Issue number7
DOIs
StatePublished - Jul 2011

Fingerprint

Spinocerebellar Ataxias
Huntington Disease
Inositol
Inositol 1,4,5-Trisphosphate Receptors
Corpus Striatum
Lipid bilayers
Purkinje Cells
Lipid Bilayers
Cell death
Neurodegenerative Diseases
Transgenic Mice
Neurons
Proteins
Cell Death
Chemical activation
Association reactions
Therapeutics
polyglutamine

Keywords

  • Apoptosis
  • Ataxin-2
  • Ataxin-3
  • Calcium signaling
  • Huntingtin
  • Inositol 1,4,5-trisphosphate
  • Memantine
  • Mitochondria
  • Neurodegeneration
  • NMDA receptor
  • Polyglutamine expansion
  • Spinocerebellar ataxias
  • Transgenic mice

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Biochemistry

Cite this

@article{6d986d3e72d34930bf32564f5200cdb7,
title = "Role of inositol 1,4,5-trishosphate receptors in pathogenesis of Huntington's disease and spinocerebellar ataxias",
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 IP 3R1 causes sensitization of IP3R1 to activation by IP 3 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 = "Apoptosis, Ataxin-2, Ataxin-3, Calcium signaling, Huntingtin, Inositol 1,4,5-trisphosphate, Memantine, Mitochondria, Neurodegeneration, NMDA receptor, Polyglutamine expansion, Spinocerebellar ataxias, Transgenic mice",
author = "Ilya Bezprozvanny",
year = "2011",
month = "7",
doi = "10.1007/s11064-010-0393-y",
language = "English (US)",
volume = "36",
pages = "1186--1197",
journal = "Neurochemical Research",
issn = "0364-3190",
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T1 - Role of inositol 1,4,5-trishosphate receptors in pathogenesis of Huntington's disease and spinocerebellar ataxias

AU - Bezprozvanny, Ilya

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N2 - 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 IP 3R1 causes sensitization of IP3R1 to activation by IP 3 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.

AB - 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 IP 3R1 causes sensitization of IP3R1 to activation by IP 3 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.

KW - Apoptosis

KW - Ataxin-2

KW - Ataxin-3

KW - Calcium signaling

KW - Huntingtin

KW - Inositol 1,4,5-trisphosphate

KW - Memantine

KW - Mitochondria

KW - Neurodegeneration

KW - NMDA receptor

KW - Polyglutamine expansion

KW - Spinocerebellar ataxias

KW - Transgenic mice

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U2 - 10.1007/s11064-010-0393-y

DO - 10.1007/s11064-010-0393-y

M3 - Article

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AN - SCOPUS:79959863439

VL - 36

SP - 1186

EP - 1197

JO - Neurochemical Research

JF - Neurochemical Research

SN - 0364-3190

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