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Deranged neuronal calcium signaling and Huntington disease

Ilya Bezprozvanny1, Michael R Hayden

  • 1Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Ilya.Bezprozvanny@UTSouthwestern.edu

Biochemical and Biophysical Research Communications
|September 1, 2004
PubMed

Insights

Huntington disease (HD) involves abnormal calcium (Ca2+) signaling in brain cells. Expanded huntingtin protein disrupts Ca2+ balance, leading to neuron death and suggesting Ca2+ blockers as a potential treatment.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Huntington disease (HD) is an inherited neurodegenerative disorder.
  • It is caused by polyglutamine (polyQ) expansion in the huntingtin (Htt) protein.
  • The exact mechanism linking polyQ expansion to neuron death is unclear.

Purpose of the Study:

  • To investigate the link between polyQ expansion in huntingtin and disrupted calcium (Ca2+) signaling in medium spiny neurons (MSN).
  • To explore the role of Ca2+ dysregulation in the pathogenesis of Huntington disease.

Main Methods:

  • Examined Ca2+ homeostasis in mitochondria from HD patients and mouse models.
  • Assessed the effect of expanded huntingtin (Httexp) on NMDA receptor activity.
  • Investigated the interaction between Httexp and the inositol trisphosphate receptor (InsP3R1).

Main Results:

  • Abnormal Ca2+ homeostasis was observed in mitochondria from HD patients and models.
  • Httexp potentiated NMDA receptor activity in neurons.
  • Httexp sensitized InsP3R1 to activation, leading to increased cytosolic and mitochondrial Ca2+ levels.

Conclusions:

  • Aberrant cytosolic and mitochondrial Ca2+ overload in MSN is implicated in HD pathogenesis.
  • Targeting Ca2+ signaling pathways may offer a therapeutic strategy for Huntington disease.

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