Calcium dysregulation in amyotrophic lateral sclerosis

Cell Calcium. 2010 Feb;47(2):165-74. doi: 10.1016/j.ceca.2009.12.002. Epub 2010 Jan 29.


In the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS), motor neurons degenerate with signs of organelle fragmentation, free radical damage, mitochondrial Ca2+ overload, impaired axonal transport and accumulation of proteins in intracellular inclusion bodies. Subgroups of motor neurons of the brainstem and the spinal cord expressing low amounts of Ca2+ buffering proteins are particularly vulnerable. In ALS, chronic excitotoxicity mediated by Ca2+-permeable AMPA type glutamate receptors seems to initiate a self-perpetuating process of intracellular Ca2+ dysregulation with consecutive endoplasmic reticulum Ca2+ depletion and mitochondrial Ca2+ overload. The only known effective treatment, riluzole, seems to reduce glutamatergic input. This review introduces the hypothesis of a "toxic shift of Ca2+" within the endoplasmic reticulum-mitochondria Ca2+ cycle (ERMCC) as a key mechanism in motor neuron degeneration, and discusses molecular targets which may be of interest for future ERMCC modulating neuroprotective therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Brain Stem / pathology
  • Calcium / metabolism*
  • Calcium Signaling*
  • Cell Death
  • Humans
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Neuroprotective Agents / therapeutic use
  • Receptors, AMPA / metabolism
  • Riluzole / therapeutic use
  • Spinal Cord / pathology


  • Neuroprotective Agents
  • Receptors, AMPA
  • Riluzole
  • Calcium