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

Calcium dysregulation in amyotrophic lateral sclerosis.

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1
Dept. of Neurology, Friedrich-Schiller University Hospital Jena, Erlanger Allee 101, 07747 Jena, Germany. julian.grosskreutz@med.uni-jena.de

Abstract

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.

PMID:
20116097
DOI:
10.1016/j.ceca.2009.12.002
[Indexed for MEDLINE]
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