Is there a functional role for KCNMA1 in the multiple sclerosis?

Abstract

Purpose/Objective: A more detailed insight into disease mechanisms of multiple sclerosis (MS) is crucial for the development of new and more effective theories. MS is a chronic inflammatory autoimmune disease of the central nervous system. The aim of this study is to identify novel disease associated proteins that are functionally involved in the MS brain pathology. Materials and methods: In a previous proteomics study, brainstem proteins were obtained from Lewis rats with MBP induced acute experimental autoimmune encephalomyelitis (EAE), a well characterized disease model of MS. Samples were collected at different time points: just before onset of symptoms, at the top of the disease and following recovery. To analyze changes in the brainstem proteome during the disease course, a quantitative proteomics study was performed using two-dimensional difference in-gel electrophoresis (2D-DIGE) followed by mass spectrometry. Results: We identified 75 proteins with a significant abundance difference between the different disease stages. Regulated proteins were mapped to existing biological networks by Ingenuity Pathway Analysis (IPA). Post-synaptic density protein 95 (DLG4), a key player in neuronal signalling and calcium-activated potassium channel alpha 1(KCNMA1), involved in neurotransmitter release, are 2 putative regulators connecting 64% of the proteins identified. The involvement of KCNMA1 in macrophage functionality was studied in vitro by using a specific functional blocker for KCNMA1, paxillin. We show that blocking of KCNMA1 altered myelin phagocytosis and proinflammatory cytokine release, disease mechanisms which are highly involved in EAE and MS pathology. We are currently investigating possible influences of this blocker on functionality of other disease relevant cells and processes using in vitro and in vivo models. Conclusions: This study will elucidate to what extent modulation via this ion channel affects disease processes in the context of EAE/MS.

Publication appears at doi: 10.1111/imm.12002