Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression

Tortarolo, Massimo; Veglianese, Pietro; Calvaresi, Novella; Botturi, A.; Rossi, Chiara; Giorgini, Andrea; Migheli, Antonio; Bendotti, Caterina

doi:10.1016/s1044-7431(03)00022-8

Cited by 161 publications

(112 citation statements)

References 41 publications

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“…Marked activation of microglia and astrocytes, and cytokine overexpression (that is, TNF-α), were commonly detected in the SOD1 transgenic mouse (48)(49)(50) and in the wobbler mouse. The wobbler mouse shows earlyonset selective motor neuron death in the cervical spinal cord (37) accompanied by glial activation (21)(22)(23) and upregulation of TNF-α (24) and the activation of both jun N-terminal kinase (JNK) and p38 mitogen-activated stress kinase (p38MAPK) in glial cells and neurons at the early phases of symptom progression (38).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

Paola

Mariani

Bigini

et al. 2012

Mol Med

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Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteriaderived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle-and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

Paola

Mariani

Bigini

et al. 2012

Mol Med

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“…All of these are Ser/ Thr-Pro motifs, which makes them targets for proline-directed kinases such as members of the stress-activated protein kinase family (c-Jun amino-terminal kinases and p38) and Cdks. Interestingly, aberrant activation of both p38 and cdk5 (a neuronal Cdk) are seen in ALS and mutant SOD1 transgenic models of ALS, and this activation may be part of mutant SOD1 toxicity (45)(46)(47)(48)(49)(50)(51). However, mutation of these sites did not noticeably alter the effect of ALS2 on Rac activity.…”

Section: Discussionmentioning

confidence: 99%

ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth

Tudor

Perkinton

Schmidt

et al. 2005

Journal of Biological Chemistry

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Rac and its downstream effectors p21-activated kinase (PAK) family kinases regulate actin dynamics within growth cones to control neurite outgrowth during development. The activity of Rac is stimulated by guanine nucleotide exchange factors (GEFs) that promote GDP release and GTP binding. ALS2/Alsin is a recently described GEF that contains a central domain that is predicted to regulate the activities of Rac and/or Rho and Cdc42 activities. Mutations in ALS2 cause some recessive familial forms of amyotrophic lateral sclerosis (ALS) but the function of ALS2 is poorly understood. Here we demonstrate that ALS2 is present within growth cones of neurons, in which it co-localizes with Rac. Furthermore, ALS2 stimulates Rac but not Rho or Cdc42 activities, and this induces a corresponding increase in PAK1 activity. Finally, we demonstrate that ALS2 promotes neurite outgrowth. Defects in these functions may therefore contribute to motor neuron demise in ALS.

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“…The sections were blocked in phosphate-buffered saline containing 5% normal goat serum and 0.05% TX for 60 min at room temperature and then incubated with anti-ubiquitin antibody (DakoCytomation) diluted 1:750. The sections were incubated with the anti-rabbit biotinylated antiserum (Vector Laboratories, diluted 1:500), and the immune reaction was revealed by the tyramide signal amplification kit (Cy5; PerkinElmer Life Sciences), as described (29). After the ubiquitin staining, a second staining was done with the anti-hSOD1 antibody (Upstate Biotechnology, Inc.) diluted 1:2000.…”

Section: Methodsmentioning

confidence: 99%

Insoluble Mutant SOD1 Is Partly Oligoubiquitinated in Amyotrophic Lateral Sclerosis Mice

Basso

Massignan

Giuseppina

et al. 2006

Journal of Biological Chemistry

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Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS) through an unknown gain-of-function mechanism. Mutant SOD1 aggregation may be the toxic property. In fact, proteinaceous inclusions rich in mutant SOD1 have been found in tissues from the familial form of ALS patients and in mutant SOD1 animals, before disease onset. However, very little is known of the constituents and mechanism of formation of aggregates in ALS. We and others have shown that there is a progressive accumulation of detergent-insoluble mutant SOD1 in the spinal cord of G93A SOD1 mice. To investigate the mechanism of SOD1 aggregation, we characterized by proteome technologies SOD1 isoforms in a Triton X-100-insoluble fraction of spinal cord from G93A SOD1 mice at different stages of the disease. This showed that at symptomatic stages of the disease, part of the insoluble SOD1 is unambiguously mono-and oligoubiquitinated, in spinal cord and not in hippocampus, and that ubiquitin branches at Lys 48 , the major signal for proteasome degradation. At presymptomatic stages of the disease, only insoluble unmodified SOD1 is recovered. Partial ubiquitination of SOD1-rich inclusions was also confirmed by immunohistochemical and electron microscopy analysis of lumbar spinal cord sections from symptomatic G93A SOD1 mice. On the basis of these results, we propose that ubiquitination occurs only after SOD1 aggregation and that oligoubiquitination may underline alternative mechanisms in disease pathogenesis.

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Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression

Cited by 161 publications

References 41 publications

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth

Insoluble Mutant SOD1 Is Partly Oligoubiquitinated in Amyotrophic Lateral Sclerosis Mice

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