Abstract
MECP2 and its product methyl-CpG binding protein 2 (MeCP2) are associated with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), which are inflammatory, autoimmune, and demyelinating disorders of the central nervous system (CNS). However, the mechanisms and pathways regulated by MeCP2 in immune activation in favor of MS and NMOSD are not fully understood. We summarize findings that use the binding properties of MeCP2 to identify its targets, particularly the genes recognized by MeCP2 and associated with several neurological disorders. MeCP2 regulates gene expression in neurons, immune cells and during development by modulating various mechanisms and pathways. Dysregulation of the MeCP2 signaling pathway has been associated with several disorders, including neurological and autoimmune diseases. A thorough understanding of the molecular mechanisms underlying MeCP2 function can provide new therapeutic strategies for these conditions. The nervous system is the primary system affected in MeCP2-associated disorders, and other systems may also contribute to MeCP2 action through its target genes. MeCP2 signaling pathways provide promise as potential therapeutic targets in progressive MS and NMOSD. MeCP2 not only increases susceptibility and induces anti-inflammatory responses in immune sites but also leads to a chronic increase in pro-inflammatory cytokines gene expression (IFN-γ, TNF-α, and IL–1β) and downregulates the genes involved in immune regulation (IL-10, FoxP3, and CX3CR1). MeCP2 may modulate similar mechanisms in different pathologies and suggest that treatments for MS and NMOSD disorders may be effective in treating related disorders.
Graphical Abstract
MeCP2 regulates gene expression in MS and NMOSD. However, dysregulation of the MeCP2 signaling pathway is implicated in these disorders. MeCP2 plays a role as a therapeutic target for MS and NMOSD and provides pathways and mechanisms that are modulated by MeCP2 in the regulation of gene expression.
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Data Availability
All processed data used in this review can be obtained from the corresponding author upon reasonable request.
Abbreviations
- ADCC:
-
Antibody-dependent cellular cytotoxicity
- AQP4:
-
Aquaporin 4
- AQP4-IgG-:
-
AQP4-IgG-negative
- AQP4-IgG+ :
-
AQP4-IgG-positive
- BBB:
-
Blood–brain barrier
- BCMA:
-
B cell maturation antigen
- BDNF:
-
Brain-derived neurotrophic factor
- C:
-
Complement
- CARs:
-
Chimeric antigen receptors
- CDC:
-
Complement-dependent cytotoxicity
- CMT:
-
Charcot-Marie-Tooth
- CNS:
-
Central nervous system
- CREB1:
-
CAMP response element-binding protein 1
- CSF:
-
Cerebrospinal fluid
- DNMT:
-
DNA methyltransferase
- dpi:
-
Days post-induction
- DRG:
-
Dorsal root ganglia
- EAE:
-
Experimental autoimmune encephalomyelitis
- FoxP3+ :
-
Forkhead box P3
- GA:
-
Glatiramer acetate
- GAP-43:
-
Growth-associated protein 43
- GFAP:
-
Glial fibrillary acidic protein
- GN:
-
Glossopharyngeal neuralgia
- GWAS:
-
Genome-wide association studies
- HAT:
-
Histone acetyltransferase
- HDAC:
-
Histone deacetylase
- HLA :
-
Human leukocyte antigen
- IBA1 :
-
Ionized calcium-binding adaptor molecule 1
- IFN-γ:
-
Gamma interferon
- IGF:
-
Insulin growth factor
- Igs:
-
Immunoglobulins
- IL:
-
Interleukin
- INO:
-
Internuclear ophthalmoplegia
- KAT:
-
Lysine acetyltransferase
- KO:
-
Knockout
- LESCLs:
-
Longitudinally extensive spinal cord lesions
- LETM:
-
Longitudinally extensive transverse myelitis
- MAG:
-
Myelin-associated glycoprotein
- MBDs:
-
Methyl-CpG binding domains
- MBP:
-
Myelin basic protein
- MeCP2:
-
Product methyl-CpG-binding protein 2
- MHC :
-
Major histocompatibility complex
- miRNAs:
-
MicroRNAs
- MMF:
-
Mycophenolate mofetil
- MMP:
-
Matrix metalloproteinase
- MOG:
-
Myelin oligodendrocyte glycoprotein
- MS:
-
Multiple sclerosis
- MUT:
-
Mutant
- ncRNAs:
-
Non-coding RNAs
- NGF:
-
Nerve growth factor
- NK:
-
Natural killer
- NMO:
-
Neuromyelitis optica
- NMOSD:
-
Neuromyelitis optica spectrum disorders
- NTR:
-
Neurotrophin receptor
- OAPs:
-
Orthogonal arrays of particles
- OG:
-
Oligodendrocyte
- ON:
-
Optic neuritis
- OPCs:
-
Oligodendrocyte precursor cells
- PBMCs:
-
Peripheral blood mononuclear cells
- PheWAS:
-
Phenome-wide association studies
- PNS:
-
Peripheral nervous system
- PPMS:
-
Primary progressive MS
- RRMS:
-
Relapsing–remitting MS
- RTT:
-
Rett syndrome
- SCI:
-
Spinal cord injury
- SNP:
-
Single-nucleotide polymorphism
- SPMS:
-
Secondary progressive phase
- SVZ:
-
Subventricular zone
- TGF:
-
Tumor growth factor
- Th17:
-
T helper 17
- TN:
-
Trigeminal neuralgia
- TNFR:
-
Tumor necrosis factor receptor
- TNF-α:
-
Tumor necrosis factor-alpha
- TRD:
-
Transcriptional repressor domain
- Treg:
-
Regulatory T
- Trk(B):
-
Tropomyosin-related kinase(receptor B)
- TrkB+ :
-
TrkB-positive
- TSA:
-
Trichostatin A
- TSPO:
-
Translocator protein
- WT:
-
Wild-type
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The authors would like to acknowledge the technical support provided by the National Natural Science Foundation of China.
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This review was supported by the Medical Research Project of Hebei Province (No. 20210312).
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AM designed the review. SS and RG created the figures. AH and MS collected the literature review data. HA, IA and RU proofread the manuscript. BL supervised the review. All the authors have approved the submission.
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Mehmood, A., Shah, S., Guo, RY. et al. Methyl-CpG-Binding Protein 2 Emerges as a Central Player in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders. Cell Mol Neurobiol 43, 4071–4101 (2023). https://doi.org/10.1007/s10571-023-01432-7
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DOI: https://doi.org/10.1007/s10571-023-01432-7