title: Calcium dysregulation in amyotrophic lateral sclerosis.
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.
authors.affiliation: Dept. of Neurology, Friedrich-Schiller University Hospital Jena, Erlanger Allee 101, 07747 Jena, Germany. julian.grosskreutz@med.uni-jena.de
authors.forename: Julian
authors.initials: J
authors.lastname: Grosskreutz
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Bernhard U
authors.initials: BU
authors.lastname: Keller
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001933:Brain Stem / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D016923:Cell Death; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D018091:Receptors, AMPA / Q000378:metabolism; D019782:Riluzole / Q000627:therapeutic use; D013116:Spinal Cord / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D019782:Riluzole; D002118:Calcium