Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of the disease manifestation and progression, ALS patients show protein aggregates in the motor cortex and spinal cord tissue, which is believed to be at least partially caused by aberrant phase separation and the formation of persistent stress granules. Consistent with this notion, many studies have implicated cellular stress, such as ER stress, DNA damage, oxidative stress, and growth factor depletion, in ALS conditions. The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death. Here we summarize the fundamental role of MAPK in physiology and ALS pathogenesis. We also discuss pharmacological inhibitors targeting this pathway tested in pre-clinical models, suggesting their role as potential drug candidates.

C-Jun N-terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-mediated ALS and FTD

“…Next, we tested whether Bsk is hyperactive in neurons expressing G 4 C 2 repeats. Bsk/JNK belongs to the mitogen-activated protein kinase (MAPK) family, which is activated by JNK kinases (Kim & Choi, 2010; Sahana & Zhang, 2021). Upon activation, Bsk/JNK activates the transcription of downstream genes, including its inhibitor, JNK phosphatase (fly homolog: puckered , or puc ).…”

Epidrugs in Amyotrophic Lateral Sclerosis/Frontotemporal Dementia: Contextualizing a Role for Histone Kinase Inhibition in Neurodegenerative Disease

“…The mitogen-activated protein kinase (MAPK) pathway has also been implicated in neurodegeneration . This pathway regulates cell proliferation, differentiation, survival, and death.…”

“…This pathway regulates cell proliferation, differentiation, survival, and death. Several ALS-associated cellular pathophysiological defects can be linked back to abnormal phosphorylation of MAPK members, particularly MAP4K (MAP kinase kinase kinase kinase), making it a new target for novel therapeutics . Extracellular stimuli allow for the phosphorylation of MAP4K HGK (hepatocyte progenitor kinase-like/germinal center kinase-like kinase), triggering a cascade that leads to the phosphorylation of JNK (c-Jun N-terminal kinase).…”

Transcriptomic and Network Meta-Analysis of Frontotemporal Dementias

“…Similarly, dysregulation of MAPK signaling has been associated with ALS. MAPK members are the serine and threonine kinases that play a pivotal role in cellular proliferation, differentiation, apoptosis, and survival (Sahana and Zhang, 2021). Aggregates of abnormally phosphorylated MAPK components and TDP-43 have been found in motor neurons and spinal cord cells of ALS patients under stress conditions (Ayala et al, 2011).…”

“…This aberrant hyperphosphorylation of MAPK members is associated with several pathophysiological defects involved in ALS including oxidative stress, neuroinflammation, and axonal transport disruption (Ayala et al, 2011). Several MAPK inhibitors have shown promise in various cellular and animal models of ALS and one inhibitor is currently being tested in clinical trials (Sahana and Zhang, 2021). The pathway convergence between ALS and FTD suggests that MAPK inhibitors might represent a potential therapeutic option for FTD patients.…”