title: Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca(2+) permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca(2+) influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans.
authors.affiliation: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Groom
authors.forename: Iris
authors.initials: I
authors.lastname: Bresink
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Kornau
authors.forename: Vanya
authors.initials: V
authors.lastname: Stefovska
authors.forename: Gerald
authors.initials: G
authors.lastname: Müller
authors.forename: Bettina
authors.initials: B
authors.lastname: Hartmann
authors.forename: Karsten
authors.initials: K
authors.lastname: Tschauner
authors.forename: Stefan
authors.initials: S
authors.lastname: Waibel
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
authors.forename: Lechoslaw
authors.initials: L
authors.lastname: Turski
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D003035:Cobalt / Q000378:metabolism; D004576:Electromyography; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D012018:Reflex / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D021122:Protein Subunits; D018091:Receptors, AMPA; C000606290:SOD1 protein, human; C115953:glutamate receptor type B; D003035:Cobalt; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium