Deranged neuronal calcium signaling and Huntington disease

Ilya Bezprozvanny, Michael R. Hayden

Research output: Contribution to journalArticle

189 Scopus citations

Abstract

Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Httexp and MSN neurodegeneration remains elusive. Here we discuss recent data that link polyQ expansion in Httexp and deranged Ca2+ signaling in MSN neurons. Experimental evidence indicates that (1) Ca2+ homeostasis is abnormal in mitochondria isolated from lymphoblasts of HD patients and from brains of the YAC72 HD mouse model; (2) Httexp leads to potentiation of NR1/NR2B NMDA receptor activity in heterologous expression systems and in MSN from YAC72 HD mouse model; and (3) Htt exp binds to the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) carboxy-terminus and causes sensitization of InsP 3R1 to activation by InsP3 in planar lipid bilayers and in MSN. Based on these results we propose that Httexp-induced cytosolic and mitochondrial Ca2+ overload of MSN plays an important role in the pathogenesis of HD and that Ca2+ signaling blockers may play a beneficial role in treatment of HD.

Original languageEnglish (US)
Pages (from-to)1310-1317
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume322
Issue number4
DOIs
StatePublished - Oct 1 2004

Keywords

  • Apoptosis
  • Calcium signaling
  • Huntingtin
  • Inositol 1,4,5-trisphosphate
  • Mitochondria
  • NMDA
  • Neurodegeneration
  • Polyglutamine expansion

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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