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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons, which causes muscle weakness, atrophy, paralysis, and eventually death
We focus on an important cellular stress response pathway, the mitogen-activated protein kinase (MAPK) pathway, and its role in ALS
Studies in recent years have shown that ALS pathogenesis and disease progression involve many pathophysiological defects intra- and inter-cellularly connected, depicting the contribution of both neurons and glia
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons, which causes muscle weakness, atrophy, paralysis, and eventually death. ALS every year in the United States, and the life expectancy of these people is 2–5 years after diagnosis. ALS is known as Lou Gehrig’s disease in the United States, named after one of the most famous baseball players, Lou Gehrig. ALS can be associate with frontotemporal dementia (FTD), another fatal neurodegenerative disease characterized by frontotemporal lobe degeneration. ALS and FTD can be caused by the same mutations, affect the same individuals or patients from the same family, and share the same pathology. They are considered in a common disease spectrum [2,3]. We include FTD cases that are related to ALS
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