Journal
JOURNAL OF NEUROPHYSIOLOGY
Volume 109, Issue 11, Pages 2803-2814Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/jn.00500.2012
Keywords
amyotrophic lateral sclerosis; motoneuron degeneration; sodium channel; hyperexcitability
Categories
Funding
- ALS Therapy Alliance-CVS Pharmacy
- Fondecyt [1101012, 1100983]
- Conicyt-Anillo [ACT-1114, ACT-1113]
- Conicyt [24090204]
- VRID-USACH
- National Institute of Neurological Disorders and Stroke [1R01 NS-050557, RC2 NS-070-342]
- ALS Therapy Alliance, Project ALS
- Angel Fund
- Pierre L. de Bourgknecht ALS Research Foundation
- Al-Athel ALS Research Foundation
- ALS Family Charitable Foundation
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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 (PCNa), 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.
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