Abstract
Acid‐sensing ion channels (ASICs) are proton‐gated channels involved in multiple biological functions such as: pain modulation, mechanosensation, neurotransmission, and neurodegeneration. Earlier, we described the genetic association, within the Nuoro population, between Multiple Sclerosis (MS) and rs28936, located in ASIC2 3′UTR. Here we investigated the potential involvement of ASIC2 in MS inflammatory process. We induced experimental autoimmune encephalomyelitis (EAE) in wild‐type (WT), knockout Asic1−/− and Asic2−/− mice and observed a significant reduction of clinical score in Asic1−/− mice and a significant reduction in the clinical score in Asic2−/− mice in a limited time window (i.e., at days 20–23 after immunization). Immunohistochemistry confirmed the reduction in adaptive immune cell infiltrates in the spinal cord of EAE Asic1−/− mice. Analysis of mechanical allodynia, showed a significant higher pain threshold in Asic2−/− mice under physiological conditions, before immunization, as compared to WT mice and Asic1−/−. A significant reduction in pain threshold was observed in all three strains of mice after immunization. More importantly, analysis of human autoptic brain tissue in MS and control samples showed an increase of ASIC2 mRNA in MS samples. Subsequently, in vitro luciferase reporter gene assays, showed that ASIC2 expression is under possible miRNA regulation, in a rs28936 allele‐specific manner. Taken together, these findings suggest a potential role of ASIC2 in the pathophysiology of MS.
Highlights
Over the last decade, genetic research on Multiple Sclerosis (MS) has led to the discovery of more than 100 non-Major Histocompatibility Complex multiple sclerosis (MS) (MHC) (Major Histocompatibility Complex) susceptibility variants, which play an important role in both the innate and the adaptive immune system, with a prominent representation of the latter (Consortium et al, 2011; Patsopoulos et al, 2011; Beecham et al, 2013; Dendrou et al, 2015; Lill et al, 2015; Moutsianas et al, 2015)
The genetic association between rs28936 in the 3’UTR of ASIC2 and MS observed in Nuoro population (Bernardinelli et al, 2007), the evidence that ASIC1 is involved in the pathogenesis of EAE on animal model (Friese et al, 2007) and the altered expression of sodium channels reported in MS (Waxman, 2001) lead us to hypothesize that ASIC2, with which ASIC1 interacts forming heteromultimeric channels, could be an important contributor to neuropathological processes in MS
We do not have any explanation for this effect. These results suggest that despite the fact that ASIC1 seems to play a major role in EAE severity, ASIC2 is involved, probably as a consequence of the physical interaction existing between the two channels
Summary
Genetic research on Multiple Sclerosis (MS) has led to the discovery of more than 100 non-MHC (Major Histocompatibility Complex) susceptibility variants, which play an important role in both the innate and the adaptive immune system, with a prominent representation of the latter (Consortium et al, 2011; Patsopoulos et al, 2011; Beecham et al, 2013; Dendrou et al, 2015; Lill et al, 2015; Moutsianas et al, 2015). ASIC1 and ASIC2 subunits often colocalize in multiple brain regions, despite the differences observed in certain brain areas (Price et al, 2014) Our interest in this class of genes, and in particular on ASIC2, was further motivated by literature evidence showing that ASIC channels are involved in multiple biological functions such as: pain modulation, mechanosensation, acidosis-induced neuronal death and neurotransmission (Sherwood et al, 2011; Kang et al, 2012; Kweon & Suh, 2013; Wemmie et al, 2013; Ortega-Ramírez et al, 2017). A further aim was to replicate the results obtained for ASIC1 by a previous study in EAE mice (Friese et al, 2007) and to interpret them jointly with those obtained for ASIC2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
