Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system

Abstract

Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) is permeable to Na+ and Ca2+, and excessive accumulation of these ions is associated with axonal degeneration. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1-/- mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro. Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1-/- mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.

The molecular basis of neurodegeneration in multiple sclerosis

“…Regarding neuroprotection the cascade of events could be targeted at several levels, including the blockade of cytotoxic microglia activation, reducing radical production, trying to detoxify radicals by scavengers or augmenting intrinsic anti-oxidant defense mechanisms. Another option would be to reduce the downstream consequences of energy deficiency for instance by blockade of ion transporters or ion exchangers [31,98]. Several of these strategies are currently tested in MS patients and show promising results.…”

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.…”

“…5,6,[39][40][41] Tissue acidosis is one of the common symptoms shared by these diseases 5,6,[39][40][41] and considered as the cause of ASIC1a-mediated neuronal damage. 5,6,[39][40][41] Notably, mitochondria play essential roles in all these diseases.…”

“…5,6,[39][40][41] Tissue acidosis is one of the common symptoms shared by these diseases 5,6,[39][40][41] and considered as the cause of ASIC1a-mediated neuronal damage. 5,6,[39][40][41] Notably, mitochondria play essential roles in all these diseases. 10,14,26,42 Taken ischemic stroke as an example, ASIC1a gene deletion has been shown to protect against ischemic brain damage in the rodent focal ischemia/ reperfusion model, middle cerebral artery occlusion.…”

Proton production, regulation and pathophysiological roles in the mammalian brain

“…To date, several lines of evidence show that ASIC1a is involved in spine development [70] , synaptic plasticity, spatial learning [4] , and fear memory [71,72] . Under pathological conditions of 7 tissue acidosis, activation of ASIC1a channels contributes to axon degeneration [73] , ischemic neuronal death [66,74,75] , chronic pain [76] and termination of epileptic seizures [77] .…”