Induction of the immediate early gene c-jun in human spinal cord in amyotrophic lateral sclerosis with concomitant loss of NMDA receptor NR-1 and glycine transporter mRNA

Virgo, L.; Belleroche, Jacqueline de

doi:10.1016/0006-8993(95)00052-r

Cited by 56 publications

(29 citation statements)

References 34 publications

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“…Strikingly, we found that the AP1 complex member JUN was expressed at significantly higher levels in MNs compared with non-MNs, suggesting a role of JUN in maintaining MN homeostasis. This observation is in concordance with in situ hybridization data in human spinal cord tissue where JUN mRNA was found to be most abundant in MNs compared with other layers of the spinal cord, with further increases in transcript levels observed in spinal tissue of ALS patients (Virgo and de Belleroche, 1995). Hence, hyperactivation of JUN in ALS MNs may disrupt the homeostatic program, thereby driving degeneration.…”

Section: Discussionsupporting

confidence: 90%

Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis

et al. 2017

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SummaryAlthough mutations in several genes with diverse functions have been known to cause amyotrophic lateral sclerosis (ALS), it is unknown to what extent causal mutations impinge on common pathways that drive motor neuron (MN)-specific neurodegeneration. In this study, we combined induced pluripotent stem cells-based disease modeling with genome engineering and deep RNA sequencing to identify pathways dysregulated by mutant SOD1 in human MNs. Gene expression profiling and pathway analysis followed by pharmacological screening identified activated ERK and JNK signaling as key drivers of neurodegeneration in mutant SOD1 MNs. The AP1 complex member JUN, an ERK/JNK downstream target, was observed to be highly expressed in MNs compared with non-MNs, providing a mechanistic insight into the specific degeneration of MNs. Importantly, investigations of mutant FUS MNs identified activated p38 and ERK, indicating that network perturbations induced by ALS-causing mutations converge partly on a few specific pathways that are drug responsive and provide immense therapeutic potential.

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Section: Discussionsupporting

confidence: 90%

Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis

et al. 2017

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“…In fact, Virgo and Belleroche (1995) have reported a loss of GLYT1 mRNA expression in the spinal cord of humans with amyotrophic lateral sclerosis, suggesting that the deficit affects synaptic inactivation of glycine and potentially promotes the action of glutamate at NMDA receptor sites. In addition, Supplisson et a1.…”

Section: Day(s)mentioning

confidence: 99%

Differential Expressions of Glycine Transporter 1 and Three Glutamate Transporter mRNA in the Hippocampus of Gerbils with Transient Forebrain Ischemia

Fujita

Sato

Wen

et al. 1999

J Cereb Blood Flow Metab

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“…Increased expression of c-Jun has also been detected in specimens from patients with Alzheimer's disease [Anderson et al, 1996;MacGibbon et al, 1997], amyotrophic lateral sclerosis [Virgo and Belleroche, 1995] and multiple sclerosis [Martin et al, 1996]. Furthermore, the increase in c-Jun immunoreactivity (IR) has been described in degenerating neurons of animal models of Parkinson's disease [Gearan et al, 2001] and amyotrophic lateral sclerosis [Jaarsma et al, 1996].…”

Section: Introductionmentioning

confidence: 83%

Involvement of c-Jun-JNK Pathways in the Regulation of Programmed Cell Death of Developing Chick Embryo Spinal Cord Motoneurons

Ribera

Ayala²,

Casas³

2006

Dev Neurosci

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Key features of developmentally regulated programmed cell death (PCD) have been described for the first time in the chick nervous system. JNK/c-Jun pathway was involved in early events determining normal and pathological neuronal death as shown in experimental models. In the chick embryo, PCD of motoneurons (MNs) in ovo occurs within a well-defined temporal window and can be subjected to experimental manipulation. Taking advantage of this in vivo system, we explored the role of c-Jun and JNK pathway in the regulation of PCD in MNs. By using specific antibodies against phospho-c-Jun (Ser 63, 73) and JNK we demonstrated that before MNs acquire apoptotic phenotype there is an increase in c-Jun. Blockage of neuromuscular activity by the GABA agonist muscimol reduces PCD and diminishes c-Jun immunoreactivity in MNs. Extensive induction of PCD, either due to injection of β-bungarotoxin or limb bud removal, is also preceded by an increase in c-Jun immunoreactivity that is also associated with upregulation of phospho-c-Jun and JNK. Translocation of JNK from cytoplasm to MN nuclei was also detected. After acute application of β-bungarotoxin, which is a strong apoptotic stimulus for MNs, c-Jun phosphorylation occurs on serine 73, whereas serine 63 is the main site for c-Jun phosphorylation after limb bud removal. These results demonstrated that the JNK/c-Jun pathway is involved in the decision phase of normal and induced apoptosis in MNs. Pharmacological interventions involving this pathway should be explored as a potential therapeutic target for promoting MN survival.

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Induction of the immediate early gene c-jun in human spinal cord in amyotrophic lateral sclerosis with concomitant loss of NMDA receptor NR-1 and glycine transporter mRNA

Cited by 56 publications

References 34 publications

Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis

Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis

Differential Expressions of Glycine Transporter 1 and Three Glutamate Transporter mRNA in the Hippocampus of Gerbils with Transient Forebrain Ischemia

Involvement of c-Jun-JNK Pathways in the Regulation of Programmed Cell Death of Developing Chick Embryo Spinal Cord Motoneurons

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