Acute Ethanol Exposure Promotes Autophagy-Lysosome Pathway-Dependent ASIC1a Protein Degradation and Protects Against Acidosis-Induced Neurotoxicity

Abstract

Tissue acidosis is a common feature of brain ischemia which causes neuronal injury. Activation of acid-sensing ion channel 1a (ASIC1a) plays an important role in acidosis-mediated neurotoxicity. Acute ethanol administration has been shown to provide neuroprotective effects during ischemic stroke, but the precise mechanisms have yet to be determined. In this study, we investigated the effect of ethanol on the activity/expression of ASIC1a channels and acidosis-induced neurotoxicity. We showed that acute treatment of neuronal cells with ethanol for more than 3 h could reduce ASIC1a protein expression, ASIC currents, and acid-induced [Ca] elevation. We further demonstrated that ethanol-induced reduction of ASIC1a expression is mediated by autophagy-lysosome pathway (ALP)-dependent protein degradation. Finally, we showed that ethanol protected neuronal cells against acidosis-induced cytotoxicity, which effect was mimicked by autophagy activator rapamycin and abolished by autophagy inhibitor CQ. Together, these results indicate that moderate acute ethanol exposure can promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced neurotoxicity.

Factors and Molecular Mechanisms Influencing the Protein Synthesis, Degradation and Membrane Trafficking of ASIC1a

“…Our recent study showed that the neuroprotective effect of ethanol might be related to the regulation of ASIC1a expression in neurons against acidosis-induced neurotoxicity (Zhou et al, 2019b). It has been indicated that acute treatment of neurons with ethanol decreased ASIC1a protein expression and acid-induced [Ca 2+ ] elevation (Zhou et al, 2019b). Further evidence suggests that the downregulation of ASIC1a protein was mediated by degradation of the protein via the autophagy-lysosome pathway (Zhou et al, 2019b).…”

“…Tissue acidification and its associated activation of ASIC1a are common features of cerebral ischemia (Xiong et al, 2004). Our recent study showed that the neuroprotective effect of ethanol might be related to the regulation of ASIC1a expression in neurons against acidosis-induced neurotoxicity (Zhou et al, 2019b). It has been indicated that acute treatment of neurons with ethanol decreased ASIC1a protein expression and acid-induced [Ca 2+ ] elevation (Zhou et al, 2019b).…”

“…It has been indicated that acute treatment of neurons with ethanol decreased ASIC1a protein expression and acid-induced [Ca 2+ ] elevation (Zhou et al, 2019b). Further evidence suggests that the downregulation of ASIC1a protein was mediated by degradation of the protein via the autophagy-lysosome pathway (Zhou et al, 2019b).…”

The Role of Ubiquitin-Proteasome Pathway and Autophagy-Lysosome Pathway in Cerebral Ischemia

“…CysC is a critical determinant accounting for endogenous neuroprotection and is a promising agent for the therapy of stroke, which is mediated by preserving lysosomal membrane integrity [84]. Acute ethanol exposure alleviates acidosis-induced neurotoxicity after cerebral ischemia, which is mediated by increased acid-sensing ion channel 1a (ASIC1a) protein degradation through the autophagy-lysosome pathway [85] (Table 4).…”

“…K48-linked ubiquitin chains are predominantly introduced to be a signal for the ubiquitin-proteasome pathway, while K63-linked ubiquitin chains are known as a signal for autophagic degradation [102,103]. Despite their mode of [85] Abbreviations: TLR4: toll-like receptor 4; PF-11: pseudoginsenoside-F11; CAV1: caveolin1; NLRP3: NOD-like receptor family pyrin domain-containing 3; HHcy: hyperhomocysteinemia; CysC: cystatin C; ASIC1a: acid-sensing ion channel 1a. Oxidative Medicine and Cellular Longevity function and that their ubiquitin tags for substrate recognition are different, there is crosstalk between the ubiquitinproteasome pathway and the autophagy-lysosome pathway in the pathogenesis of cerebral ischemia.…”