Inter- and Intracellular Signaling in Amyotrophic Lateral Sclerosis: Role of p38 Mitogen-Activated Protein Kinase

Abstract

The pathogenetic processes underlying the selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are complex and still not completely understood even in the cases of inherited disease caused by mutations in the Cu/Zn superoxide dismutase-dependent (SOD1) gene. Recent evidence supports the view that ALS is not a cell-autonomous disease and that glial-neuron cross-talk, throughout cytokines and other toxic factors like the nitric oxide and superoxide, is a crucial determinant for the induction of motor neuron death. This cell-cell interaction may determine the progression of the disease through processes that are likely independent of the initial trigger and that may converge on the activation of intracellular death pathways in the motor neurons. In this review we provide support to the hypothesis that aberrant expression and activity of p38 mitogen protein-activated kinases cascade (p38MAPK) in motor neurons and glial cells may play a role in the development and progression of ALS. Increased activation of p38MAPK may phosphorylate neuron-specific substrates altering their physiological properties and it may turn on responsive genes leading to neurotoxicity.

Activation of Signal Transducer and Activator of Transcription-3 in the Spinal Cord of Sporadic Amyotrophic Lateral Sclerosis Patients

“…In addition, the fact that there was no significant correlation between the nuclear p-STAT3 levels in the ALS cases and their age at death or disease duration implies that STAT3 is continuously activated during aging and processes of this disease. These findings are consistent with evidence of long-term inflammation in ALS via persistent activation of p38 MAPK and NF-B in microglia and astrocytes [8][9][10][11] .…”

“…Previous studies have documented the involvement of glutamate toxicity and oxidative stress in ALS [4][5][6][7] . There is increasing evidence for neuroinflammation in this disease, such as (1) increased activation of the proinflammatory cell signaling enzyme p38 mitogen-activated protein kinase (MAPK) and the proinflammatory transcription factor nuclear factor-kappa B (NF-B) [8][9][10][11] , (2) increased cytosolic expression of proinflammatory enzymes [9,10,12] , (3) increased cell surface expression of cell adhesion molecules [9,10] , and (4) increased release of proinflammatory secretory proteins such as cytokines, chemokines, growth factors, and matrix metalloproteinases [9,10,13] . These proinflammatory gene products have been shown to be expressed in neurons, astrocytes, microglia, or both.…”

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

“…Staurosporin is known to induce apoptosis by activation of the caspase cascade as well as through generation of reactive oxygen species [30][31]. Treatment with H 2 O 2 results in oxidative damage as well as activation of p38 MAPK [32] that has also been implicated in ALS [33][34][35]. There are several lines of evidence that indicate that hsps can promote motoneuron survival.…”

Role of p38α in apoptosis: implication in cancer development and therapy

“…Aberrant chemistry and oxidative stress have been described to be involved in ALS development, being SOD1 (superoxide dismutase 1) the most frequently mutated gene in the inherited cases of ALS. Numerous evidences point to a role of p38 MAPK in the development and progression of ALS induced by mutations in SOD1 gene (Bendotti et al, 2004;Bendotti et al, 2005;Dewil et al, 2007;Holasek et al, 2005;Tortarolo et al, 2003). Mutant SOD1 provokes aberrant oxyradical reactions that increase the activation of p38 MAPK in motor neurons and glial cells.…”

“…Mutant SOD1 provokes aberrant oxyradical reactions that increase the activation of p38 MAPK in motor neurons and glial cells. This increase in active p38 MAPK may phosphorylate cytoskeletal proteins and activate cytokines and nitric oxide, thus contributing to neurodegeneration through different mechanisms including apoptosis (Bendotti et al, 2005;Tortarolo et al, 2003). 5.3-p38α in cancer therapy p38α can act as a tumor suppressor in the initial phases of malignant transformation, which involves apoptosis induction.…”