Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis
TL;DR: The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death as discussed by the authors.
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.
Citations
More filters
TL;DR: The future of epidrugs against neurodegeneration is expanded and promising novel targets underexploited thus far are discussed: histone kinases.
Abstract: Breakthroughs in understanding the epigenetic mechanisms involved in neurodegenerative disease have highlighted "epidrugs" as a potential avenue for therapeutic development. Here, we expand on the future of epidrugs against neurodegeneration and discuss promising novel targets underexploited thus far: histone kinases.
7 citations
TL;DR: In this paper, the authors compared the sporadic and familial transcriptome within the cerebellum, frontal cortex, hippocampus, and Brodmann's area 8 of patients with frontotemporal lobar degeneration to determine genes and pathways involved in the disease process.
Abstract: Frontotemporal lobar degeneration (FTLD), also known as frontotemporal dementia (FTD), results in a progressive decline in executive function, leading to behavioral changes, speech problems, and movement disorders. FTD is the second most common cause of young-onset dementia affecting approximately 50-60,000 Americans. FTD exists in familial and sporadic forms, with GRN progranulin and C9orf72 mutations being the most common causes. In this study, we compared the sporadic and familial transcriptome within the cerebellum, frontal cortex, hippocampus, and Brodmann's area 8 of patients with FTD to determine genes and pathways involved in the disease process. Most dysregulated genes expression occurred in the frontal cortex and Brodmann's area 8 for genetic and sporadic forms of FTD, respectively. A meta-analysis revealed 50 genes and 95 genes are dysregulated in at least three brain regions in patients with familial mutations and sporadic FTD patients, respectively. Familial FTD genes centered on the Wnt signaling pathway, whereas genes associated with the sporadic form of FTD centered on MAPK signaling. The results reveal the similarities and differences between sporadic and familial FTD. In addition, valproic acid and additional therapeutic agents may be beneficial in treating patients with FTD.
5 citations
TL;DR: In this paper , the authors summarize the importance of the ERK1/2 signaling pathway in the treatment of different diseases and inhibitors of ERK 1/2 in clinical or preclinical research.
3 citations
TL;DR: A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elseveier) databases was carried out to focus on the neuroprotective potential of demethyleneberberine in neurodegenerative disorders by attenuating different pathways, i.e., NF-κB, MAPK, and AMPK signalling.
2 citations
References
More filters
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Abstract: Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.
5,440 citations
TL;DR: MAPK families are discussed for their functions and cooperation with other signal pathways in regulation of cell proliferation.
Abstract: MAPK families play an important role in complex cellular programs like proliferation, differentiation, development, transformation, and apoptosis. At least three MAPK families have been characterized: extracellular signal-regulated kinase (ERK), Jun kinase (JNK/SAPK) and p38 MAPK. The above effects are fulfilled by regulation of cell cycle engine and other cell proliferation related proteins. In this paper we discussed their functions and cooperation with other signal pathways in regulation of cell proliferation.
2,044 citations
TL;DR: Recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS are summarized.
1,929 citations
TL;DR: Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified, and emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.
1,382 citations
TL;DR: In this paper, a mutant superoxide dismutase (SOD1) was found to induce non-cell-autonomous motor neuron killing by an unknown gain of toxicity.
1,372 citations