PMID- 28604632 OWN - NLM STAT- MEDLINE DCOM- 20180402 LR - 20181113 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 18 IP - 6 DP - 2017 Jun 12 TI - Experimental Autoimmune Encephalomyelitis (EAE)-Induced Elevated Expression of the E1 Isoform of Methyl CpG Binding Protein 2 (MeCP2E1): Implications in Multiple Sclerosis (MS)-Induced Neurological Disability and Associated Myelin Damage. LID - 10.3390/ijms18061254 [doi] LID - 1254 AB - Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF) has a beneficial role in myelin repair, these effects may be hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2) called MeCP2E1. We hypothesize that following experimental autoimmune encephalomyelitis (EAE)-induced myelin damage, the immune system induction of the pathogenic MeCP2E1 isoform hampers the myelin repair process by repressing BDNF expression. Using an EAE model of MS, we identify the temporal gene and protein expression changes of MeCP2E1, MeCP2E2 and BDNF. The expression changes of these key biological targets were then correlated with the temporal changes in neurological disability scores (NDS) over the entire disease course. Our results indicate that MeCP2E1 mRNA levels are elevated in EAE animals relative to naive control (NC) and active control (AC) animals during all time points of disease progression. Our results suggest that the EAE-induced elevations in MeCP2E1 expression contribute to the repressed BDNF production in the spinal cord (SC). The sub-optimal levels of BDNF result in sustained NDS and associated myelin damage throughout the entire disease course. Conversely, we observed no significant differences in the expression patterns displayed for the MeCP2E2 isoform amongst our experimental groups. However, our results demonstrate that baseline protein expression ratios between the MeCP2E1 versus MeCP2E2 isoforms in the SC are higher than those identified within the dorsal root ganglia (DRG). Thus, the DRG represents a more conducive environment than that of the SC for BDNF production and transport to the CNS to assist in myelin repair. Henceforth, the sub-optimal BDNF levels we report in the SC may arise from the elevated MeCP2E1 vs. MeCP2E2 ratio in the SC that creates a more hostile environment thereby preventing local BDNF production. At the level of transcript, we demonstrate that EAE-induces the pathological enhanced expression of MeCP2E1 that contributes to enhanced NDS during the entire disease course. Thus, the pathological induction of the MeCP2E1 isoform contributes to the disruption of the normal homeostatic signaling equilibrium network that exists between cytokines, neurotrophins and chemokines that regulate the myelin repair process by repressing BDNF. Our research suggests that the elevated ratio of MeCP2E1 relative to MeCP2E2 may be a useful diagnostic marker that clinicians can utilize to determine the degree of neurological disability with associated myelin damage. The elevated MeCP2E1 vs. MeCP2E2 ratios (E1/E2) in the SC prevent BDNF from reaching optimal levels required for myelin repair. Thus, the lower E1/E2 ratios in the DRG, allow the DRG to serve as a weak secondary compensatory mechanism for enhanced production and delivery of BDNF to the SC to try to assist in myelin repair. FAU - Khorshid Ahmad, Tina AU - Khorshid Ahmad T AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. khorshit@myumanitoba.ca. FAU - Zhou, Ting AU - Zhou T AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. zhout346@myumanitoba.ca. FAU - AlTaweel, Khaled AU - AlTaweel K AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. khaledta72@gmail.com. FAU - Cortes, Claudia AU - Cortes C AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. claudiacortesp@gmail.com. FAU - Lillico, Ryan AU - Lillico R AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. umlillic@myumanitoba.ca. FAU - Lakowski, Ted Martin AU - Lakowski TM AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. Ted.Lakowski@umanitoba.ca. FAU - Gozda, Kiana AU - Gozda K AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. gozdak@myumanitoba.ca. FAU - Namaka, Michael Peter AU - Namaka MP AD - College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, MB R3E 0T5, Canada. Mike.Namaka@umanitoba.ca. AD - College of Pharmacy, Third Military Medical University, Chongqing 400038, China. Mike.Namaka@umanitoba.ca. AD - Department of Medical Rehabilitation, College of Medicine, Faculty of Health Sciences, Winnipeg, MB R3E 0T6, Canada. Mike.Namaka@umanitoba.ca. AD - Department of Internal Medicine, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3A 1R9, Canada. Mike.Namaka@umanitoba.ca. LA - eng PT - Journal Article DEP - 20170612 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Methyl-CpG-Binding Protein 2) RN - 0 (Protein Isoforms) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Encephalomyelitis, Autoimmune, Experimental/genetics/*metabolism MH - Female MH - Methyl-CpG-Binding Protein 2/*genetics/metabolism MH - Mice MH - Multiple Sclerosis/physiopathology MH - Myelin Sheath/pathology/*physiology MH - Protein Isoforms MH - *Regeneration MH - Signal Transduction PMC - PMC5486076 OTO - NOTNLM OT - brain-derived neurotrophic factor (BDNF) OT - experimental autoimmune encephalomyelitis (EAE) OT - methyl CpG binding protein 2 (MeCP2) OT - multiple sclerosis (MS) OT - myelin repair OT - neurological disability scoring (NDS) COIS- The authors declare that they have no conflict of interest. This project was supported by the funding from the following agencies: Canadian Paraplegic Association (CPA), University of Manitoba Research Grants Program (URGP) and Bayshore Health Care Systems. EDAT- 2017/06/13 06:00 MHDA- 2018/04/03 06:00 PMCR- 2017/06/01 CRDT- 2017/06/13 06:00 PHST- 2017/02/21 00:00 [received] PHST- 2017/04/15 00:00 [revised] PHST- 2017/05/13 00:00 [accepted] PHST- 2017/06/13 06:00 [entrez] PHST- 2017/06/13 06:00 [pubmed] PHST- 2018/04/03 06:00 [medline] PHST- 2017/06/01 00:00 [pmc-release] AID - ijms18061254 [pii] AID - ijms-18-01254 [pii] AID - 10.3390/ijms18061254 [doi] PST - epublish SO - Int J Mol Sci. 2017 Jun 12;18(6):1254. doi: 10.3390/ijms18061254.