Understanding Abnormal c-JNK/p38MAPK Signaling in Amyotrophic Lateral Sclerosis: Potential Drug Targets and Influences on Neurological Disorders

Abstract

c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to regulate neuronal signals. The abnormal activation of these cellular signals can cause glutamate excitotoxicity, disrupted protein homeostasis, defective axonal transport, and synaptic dysfunction. Various pre-clinical and clinical findings indicate that the up-regulation of c-JNK and p38MAPK signaling is associated with neurological disorders. Exceptionally, a significant amount of experimental data has recently shown that dysregulated c-JNK and p38MAPK are implicated in the damage to the central nervous system, including amyotrophic lateral sclerosis. Furthermore, currently available information has shown that c- JNK/p38MAPK signaling inhibitors may be a promising therapeutic alternative for improving histopathological, functional, and demyelination defects related to motor neuron disabilities. Understanding the abnormal activation of c-JNK/p38MAPK signaling and the prediction of motor neuron loss may help identify important therapeutic interventions that could prevent neurocomplications. Based on the involvement of c-JNK/p38MAPK signaling in the brain, we have assumed that the downregulation of the c-JNK/p38MAPK signaling pathway could trigger neuroprotection and neurotrophic effects towards clinicopathological presentations of ALS and other brain diseases. Thus, this research-based review also outlines the inhibition of c-JNK and p38MAPK signal downregulation in the pursuit of disease-modifying therapies for ALS.