Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

• Published in: Cell death and differentiation 2013-04, Vol.20 (4), p.589-598
• Main Authors: Behan, Á T, Breen, B, Hogg, M, Woods, I, Coughlan, K, Mitchem, M, Prehn, J H M
• Format: Article
• Language: English
• Subjects: 631/378/1689/1285; 631/378/2586; 631/80/304; 692/699/375/2004; Acid Sensing Ion Channels - chemistry; Acid Sensing Ion Channels - genetics; Acid Sensing Ion Channels - metabolism; Acidosis; Acids; Acids - toxicity; Amiloride - analogs & derivatives; Amiloride - pharmacology; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Cells, Cultured; Disease Models, Animal; Health physics; Humans; Hypotheses; Hypoxia; Ischemia; Life Sciences; Longevity; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Motor Neurons - cytology; Motor Neurons - drug effects; Motor Neurons - metabolism; Mutation; Neurological disorders; Original Paper; Pathophysiology; Physiology; Spinal cord; Stem Cells; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2012.158

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca 2+ overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro , and that acidotoxicity was partially reduced in asic1a -deficient motoneuron cultures. Cross-breeding of SOD1 G93A ALS mice with asic1a -deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-( N,N -dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS.