title: Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1(G93A)) increases persistent sodium inward currents (PC(Na)), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Na(v)) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1(G93A). These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1(G93A) on motoneurons is increased excitability, an observation with direct implications for therapy of ALS.
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Ave Republica 217, Santiago, Chile.
authors.forename: Elsa
authors.initials: E
authors.lastname: Fritz
authors.forename: Pamela
authors.initials: P
authors.lastname: Izaurieta
authors.forename: Alexandra
authors.initials: A
authors.lastname: Weiss
authors.forename: Franco R
authors.initials: FR
authors.lastname: Mir
authors.forename: Patricio
authors.initials: P
authors.lastname: Rojas
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Fabiola
authors.initials: F
authors.lastname: Rojas
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Madrid
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Zundert
mesh_terms: D000200:Action Potentials; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D016923:Cell Death; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000633:toxicity; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; C000606290:SOD1 protein, human; D061567:Voltage-Gated Sodium Channel Blockers; D012964:Sodium; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium
keywords: amyotrophic lateral sclerosis; hyperexcitability; motoneuron degeneration; sodium channel