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Understanding Abnormal c-JNK/p38MAPK Signaling Overactivation Involved in the Progression of Multiple Sclerosis: Possible Therapeutic Targets and Impact on Neurodegenerative Diseases

Abstract

Demyelination, immune dysregulation, and neuroinflammation are the most common triggers of motor neuron disorders such as multiple sclerosis (MS). MS is a chronic demyelinating neurodegenerative disease of the central nervous system caused by abnormal immune activation, which causes myelin sheath damage. Cell signal transduction pathways are required for a variety of physiological and pathological processes in the brain. When these signaling systems become overactive, they can lead to disease progression. In various physiological conditions, abnormal mitogen-activated protein kinase (MAPK) activation is associated with several physiological dysfunctions that cause neurodegeneration. Previous research indicates that c-JNK and p38MAPK signaling play critical roles in neuronal growth and differentiation. c-JNK/p38MAPK is a member of the MAPK family, which regulates metabolic pathways, cell proliferation, differentiation, and apoptosis that control certain neurological activities. During brain injuries, c-JNK/p38MAPK also affects neuronal elastic properties, nerve growth, and cognitive processing. This review systematically linked abnormal c-JNK/p38MAPK signaling activation to multiple neuropathological pathways in MS and related neurological dysfunctions. MS progression is linked to genetic defects, oligodendrocyte destruction, glial overactivation, and immune dysregulation. We concluded that inhibiting both the c-JNK/p38MAPK signaling pathways can promote neuroprotection and neurotrophic effects against the clinical-pathological presentation of MS and influence other neurological disorders. As a result, the potential benefits of c-JNK/p38MAPK downregulation for the development of disease-modifying treatment interventions in the future could include MS prevention and related neurocomplications.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ASK1:

Apoptosis signal-regulating kinase 1

BBB:

Blood-brain barrier

Bcl-2:

B cell lymphoma 2

Bcl-Xl:

B cell lymphoma-extra large

CD-4:

Cluster of differentiation 4

c-JNK:

C-Jun N-terminal kinase

CNS:

Central nervous system

DNA:

Deoxyribonucleic acid

DA:

Dopamine

EAE:

Experimental autoimmune encephalomyelitis

GLT-1:

Glutamate

GPCR:

Protein-coupled receptors

GPRK-2:

G protein-coupled receptor kinase 2

H2O2 :

Hydrogen peroxide

HD:

Huntington’s disease

IFN-γ:

Interferon gamma

IgG:

Immunoglobulin G

IL-1:

Interleukin-1

MKK:

Mitogen-activated protein kinase kinase

MAPK:

Mitogen-activated protein kinase

MS:

Multiple sclerosis

NO:

Nitric oxide

OGD:

Oxygen-glucose deprivation

OPCs:

Oligodendrocyte progenitor cells

p38MAPK:

P38 mitogen-activated protein kinases

PD:

Parkinson’s disease

PDH:

Private dehydrogenase

PDK:

Process design kit

PPMS:

Primary progressive multiple sclerosis

ROS:

Reactive oxygen species

RRMS:

Relapsing-remitting multiple sclerosis

SAPK:

Stress-activated protein kinase

SPMS:

Secondary progressive phase multiple sclerosis

TAK1:

Transforming growth factor beta-activated kinase 1

TCR:

T cell receptor

TNF-α:

Tumor necrosis factor alpha

UNC51:

Serine/threonine kinase involved in the autophagic cascade

UV:

Ultraviolet

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Singh, A., Upadhayay, S. & Mehan, S. Understanding Abnormal c-JNK/p38MAPK Signaling Overactivation Involved in the Progression of Multiple Sclerosis: Possible Therapeutic Targets and Impact on Neurodegenerative Diseases. Neurotox Res 39, 1630–1650 (2021). https://doi.org/10.1007/s12640-021-00401-6

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Keywords

  • Multiple sclerosis
  • c-JNK
  • p38MAPK
  • Demyelination
  • Oligodendrocytes
  • Immune dysregulation