Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca 2 þ 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. Cell Death and Differentiation (2013) 20, 589-598; doi:10.1038/cdd.2012.158; published online 11 January 2013Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition where motoneurons in the spinal cord and brain stem die, resulting in paralysis and eventual death. Despite the significant recent advances in understanding the pathophysiology and genetics of ALS, 1 there is no cure for this condition. Currently, the only FDA-approved, disease-modifying drug used for the treatment of ALS is riluzole, which inhibits neuronal glutamate, releases and stimulates glutamate uptake into astrocytes. 2 The use of riluzole is based on the hypothesis that overactivation of Ca 2 þ -permeable AMPA receptors in motoneurons results in excitotoxicity, and that this process contributes to motoneuron death in ALS. 3 Nevertheless, the disease-modifying effects of riluzole therapy are moderate and vary among patients. 4 Acid-sensing ion channels (ASICs) represent a group of ion channels activated by protons. They belong to the epithelial sodium (Na þ ) family of amiloride-sensitive cation channels, and allow for Na þ and Ca 2 þ entry into neurons. Of the six ASIC subunits cloned, ASIC1a, ASIC2a and ASIC2b are expressed in the brain and spinal cord neurons. 5 ASIC1a and ASIC2s are found in the brain regions with high synaptic density and facilitate excitatory synaptic transmission. 6,7 ASIC1a in particular is involved in nociception and fear behavior triggered by hypercapnia. 8,9 ASICs have also been investigated as new targets for the treatment of ischemic stroke and cerebral hypoxia 10 on the premise that activation of ASIC1a during ischemia ...

Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

“…1E). Our data on increasing acidosis within the lumbar spinal cord agree with recent findings in C57BL/6 SOD1 G93A mice by an alternative pH measuring method (14). Thus, as the mouse ALS disease advanced, the CNS developed progressively greater acidosis.…”

“…Interestingly, gene expression profiling studies showed significant up-regulation (2-to 10-fold) of ASIC2 (also known as amiloride-sensitive cation channel neuronal 1; ACCN1) and ASIC3 (ACCN3) in laser-captured motor neurons from patients with ALS harboring mutations in SOD1 (13), suggesting that acidosis occurs in patients with ALS. In agreement, significant upregulation of ASIC2 expression was recently noted in the spinal cords of patients with sporadic ALS and SOD1 G93A mice (14).…”

AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis

“…Concomitant with reduced pH, significant accumulation of glycogen was observed in both the CNS and visceral organs of SOD1 G93A mice [46]. Furthermore, treatment of SOD1 G93A mice with acetazolamide which promotes acidosis worsened survival [46], while deletion or pharmacological inhibition of acid sensing ion channels improved symptoms [65], suggesting a deleterious role of metabolic acidosis in ALS.…”

Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

“…10,13,15 It was reported that compared with WT mice, ASIC1a-deficient mice had both a markedly reduced motor deficit and decreased axonal degeneration in a mouse model of experimental autoimmune encephalomyelitis despite the similar levels of CNS inflammation. 39,43 Interestingly, ASIC1a was found only in the surface membrane of neuronal soma and dendrites but not that of axons. 3,44 Perturbed intracellular Ca 2 þ homeostasis was considered as a major underlying cause of this disease.…”