Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenic mice carrying amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutations develop a motoneuron disease resembling human ALS. c-Jun is a transcription factor frequently induced in injured neurons. In this study we have examined the distribution of c-Jun-immunoreactivity in the brainstem and spinal cord of transgenic SOD1 mice with a glycine 93 alanine (G93A) mutation. In non-transgenic littermates c-Jun immunostaining was predominantly situated in motoneurons. The number of c-Jun immunoreactive motoneuron was reduced in SOD1(G93A) mice due to pronounced loss of motoneurons. In SOD1(G93A) mice, however, c-Jun-immunoreactivity was strongly induced in neurons in the intermediate zone (Rexed's laminae V-VIII and X) of the spinal cord and throughout the brainstem reticular formation. These findings are of interest since increased levels of c-jun also have been found in the intermediate zone of the spinal cord of ALS patients. This c-Jun may be involved in the neurodegenerative processes both in ALS and in motoneuron disease in SOD1(G93A) mice.
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PMID:Induction of c-Jun immunoreactivity in spinal cord and brainstem neurons in a transgenic mouse model for amyotrophic lateral sclerosis. 897 9

Motor neuron diseases in humans, which include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophies (SMAs), are characterized by motorneuron loss and chromatolysis in some or many remaining cells of the anterior horn of the spinal cord. Motorneurons are filled with phosphorylated neurofilaments, and ubiquitinated filamentous and granular inclusions which conform Lewy-like bodies in ALS patients. In addition, axonal balloonings filled with phosphorylated neurofilaments are usually observed in ALS patients with predominant signs of spinal motor neuron deficits and rapid clinical course. SMAs also occur in other species. Loss of motorneurons and chromatolytic cells filled with phosphorylated neurofilaments are the main pathologic findings in the ventral horn. In both humans and animals, loss of synaptic afferents is found in chromatolytic cells but not in normally-appearing motorneurons, thus suggesting that loss of synapses is a later event in motor neuron disease. These morphological features, together with the lack of c-Jun/AP-1 immunostaining and lack of staining with the method of in situ labelling of nuclear DNA fragmentation of dying cells, are different from those found during the process of naturally occurring (programmed) cell death in normal development. Although deletions in the SMN and NAIP genes located in 5q are found in patients with SMA, the cell death programme in SMA should not be considered as a mere persistence or reactivation of naturally occurring (programmed) cell death during normal development.
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PMID:[Motor neuron diseases: a type of programmed cell death?]. 904 76

There is increasing evidence that oxidative damage plays a major role in amyotrophic lateral sclerosis (ALS), but how it contributes to motor neuron degeneration and astrocytic gliosis, two pathologic hallmarks of the disease, is unknown. A few studies have suggested that ALS motor neurons die via apoptosis and show upregulation of c-jun, an immediate early gene that is necessary for neuronal apoptosis. In order to elucidate the mechanisms of cell damage induced by oxidant stress, we have studied in ALS and control spinal cord the immunohistochemical expression of c-Jun, of JNK/SAPK, a kinase that activates c-Jun following various types of stress, and of NF-kappa B, a transcription factor that is induced by oxidant stress and has prominent neuroprotective functions. An in situ end-labeling assay was performed for detecting apoptotic cells. We show that (a) the JNK/SAPK-c-Jun pathway is dramatically overexpressed in ALS spinal cord; (b) the strongest activation occurs in astrocytes, while motor neurons show unusually low expression of the pathway; (c) increased JNK/SAPK expression in glial cells is accompanied by NF-kappa B activation, indicating the presence of a protective response to oxidant sress, which is deficient in motor neurons; (d) activation of JNK/SAPK, c-Jun and NF-kappa B is unrelated to apoptotic cell death. These results support the view that astrocytes are directly involved in the pathologic process of ALS, and might explain the selective vulnerability of motor neurons by their relative lack of antioxidant defenses.
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PMID:c-Jun, JNK/SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis. 941 80

Whether diseased motor neurones in sporadic amyotrophic lateral sclerosis (ALS) die via apoptosis is unknown. Because this relates primarily to difficulties in utilizing post-mortem tissue from end-stage disease, motor neurone degeneration in ALS spinal cord was compared with that of a model of a chronic motor neurone degeneration. Degenerating motor neurones in ALS, identified by ubiquitin immunoreactivity, did not demonstrate the morphological characteristics of apoptosis and were not c-Jun immunoreactive or TUNEL positive. A temporal analysis of spinal motor neurone death in the chronic AlCl3 neurotoxicity model of motor neurone degeneration was also undertaken. AlCl3 was administered intracisternally every 4 weeks and, at intervals of 51, 107, 156 and 267 days, evidence of apoptosis was sought by morphology, TUNEL hybridization or DNA laddering. Double-labelling immunostudies were also performed with antibodies to either c-Jun, ubiquitin or high molecular weight neurofilament (NFH) with TUNEL hybridization. Although significant neurone loss was evident, apoptosis was not found. These studies demonstrate a lack of apoptosis in ALS spinal motor neurones and suggest that this observation does not relate to the utilization of post-mortem tissue in which apoptotic neurones may have been lost.
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PMID:Motor neuronal death in sporadic amyotrophic lateral sclerosis (ALS) is not apoptotic. A comparative study of ALS and chronic aluminium chloride neurotoxicity in New Zealand white rabbits. 1084 Feb 78

In susceptible strains of mice, infection with the mutant retrovirus MoMuLV-ts1 causes a neurodegeneration and immunodeficiency syndrome that resembles human human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS). In this study the authors show increased expression of cyclooxygenase-2 (COX-2) in the brainstem tissues of ts1-infected mice. Up-regulated central nervous system (CNS) levels of this enzyme are associated with HIV-associated dementia and other inflammatory and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In brainstem sections, the authors find that astrocytes surrounding spongiform lesions contain increased amounts of immunoreactive COX-2. COX-2 is also up-regulated in cultured ts1-infected cells from the C1 astrocytic cell line, and activation of c-Jun N-terminal kinase, or JNK, pathway. Markers of endoplasmic reticulum (ER) stress, specifically the CCAAT/enhancer-binding protein (CHOP), the glucose-related protein 78 (GRP78), and phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha), were also up-regulated in ts1-infected C1 astrocytes. Up-regulation of COX-2 and the above ER signaling factors was reversed by treatment of the infected cells with curcumin which specifically inhibits the JNK/c-Jun pathway. These findings indicate that the JNK/c-Jun pathway is most likely responsible for COX-2 expression induced by ts1 in astrocytes, and that ts1 infection in astrocytes may lead to up-regulation of both inflammatory and ER stress pathways in the central nervous system. Because COX-2 inhibitors are now widely used to treat inflammatory conditions in animals and humans, this finding suggests that these drugs may be useful for therapeutic intervention in neurodegenerative syndromes as well.
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PMID:Up-regulation of astrocyte cyclooxygenase-2, CCAAT/enhancer-binding protein-homology protein, glucose-related protein 78, eukaryotic initiation factor 2 alpha, and c-Jun N-terminal kinase by a neurovirulent murine retrovirus. 1603 95

To obtain insight into the morphological and molecular correlates of motoneuron degeneration in amyotrophic lateral sclerosis (ALS) mice that express G93A mutant superoxide dismutase (SOD)1 (G93A mice), we have mapped and characterized 'sick' motoneurons labelled by the 'stress transcription factors' ATF3 and phospho-c-Jun. Immunocytochemistry and in situ hybridization showed that a subset of motoneurons express ATF3 from a relatively early phase of disease before the onset of active caspase 3 expression and motoneuron loss. The highest number of ATF3-expressing motoneurons occurred at symptom onset. The onset of ATF3 expression correlated with the appearance of ubiquitinated neurites. Confocal double-labelling immunofluorescence showed that all ATF3-positive motoneurons were immunoreactive for phosphorylated c-Jun. Furthermore, the majority of ATF3 and phospho-c-Jun-positive motoneurons were also immunoreactive for CHOP (GADD153) and showed Golgi fragmentation. A subset of ATF3 and phosphorylated c-Jun-immunoreactive motoneurons showed an abnormal appearance characterized by a number of distinctive features, including an eccentric flattened nucleus, perikaryal accumulation of ubiquitin immunoreactivity, juxta-nuclear accumulation of the Golgi apparatus and the endoplasmic reticulum, and intense Hsp70 immunoreactivity. These abnormal cells were not immunoreactive for active caspase 3. We conclude that motoneurons in ALS-SOD1 mice prior to their death and disappearance experience a prolonged sick phase, characterized by the gradual accumulation of ubiquitinated material first in the neurites and subsequently the cell body.
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PMID:ATF3 expression precedes death of spinal motoneurons in amyotrophic lateral sclerosis-SOD1 transgenic mice and correlates with c-Jun phosphorylation, CHOP expression, somato-dendritic ubiquitination and Golgi fragmentation. 1626 28

The mechanism of selective and age-dependent motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) has not been defined and the role of glutathione (GSH) in association with motor neuron death remains largely unknown. A motor neuron-like cell culture system and a transgenic mouse model were used to study the effect of cellular GSH alteration on motor neuron cell death. Exposure of NSC34 motor neuron-like cells to ethacrynic acid (EA) or l-buthionine sulfoximine (BSO) dramatically reduced the cellular GSH levels, and was accompanied by increased production of reactive oxygen species (ROS) measured by the dichlorofluorescin (DCF) fluorescent oxidation assay. In addition, GSH depletion enhanced oxidative stress markers, AP-1 transcriptional activation, c-Jun, c-Fos and heme oxygenase-1 (HO-1) expression in NSC34 cells analyzed by a luciferase reporter, Western blotting and quantitative PCR assays respectively. Furthermore, depletion of GSH decreased mitochondrial function, facilitated apoptosis inducing factor (AIF) translocation, cytochrome c release, and caspase 3 activation, and consequently led to motor neuron-like cell apoptosis. In an ALS-like transgenic mouse model overexpressing mutant G93A-Cu, Zn-superoxide dismutase (SOD1) gene, we showed that the reduction of GSH in the spinal cord and motor neuron cells is correlated with AIF translocation, caspase 3 activation, and motor neuron degeneration during ALS-like disease onset and progression. Taken together, the in vitro and in vivo data presented in the current report demonstrated that decreased GSH promotes multiple apoptotic pathways contributing, at least partially, to motor neuron degeneration in ALS.
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PMID:Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo. 1715 Mar 7

Research in multiple sclerosis (MS) has recently been focusing on the extent of neuroaxonal damage and its contribution to disease outcome. In the present study, we examined spinal cord tissue from 30 clinically well-characterized MS patients. MS, amyotrophic lateral sclerosis (ALS), and control spinal cord tissue were subjected to morphometric analysis and immunohistochemistry for markers of cell damage and regeneration. Data were related to disease duration and age at death. Here, we present evidence for substantial, nonprogressive neuronal loss on the cervical and lumbar levels early in the disease course of MS. Chromatolytic neurons and immunoreactivity for c-Jun and GAP43 were observed in the ventral gray matter in and adjacent to actively demyelinating lesions, pointing toward neuronal damage and regeneration as an early response to lesion formation.
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PMID:Substantial early, but nonprogressive neuronal loss in multiple sclerosis (MS) spinal cord. 1993 72

In normal neurons, neurofilament (NF) proteins are phosphorylated in the axonal compartment. However, in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), NF proteins are aberrantly hyperphosphorylated within the cell bodies. The aberrant hyperphosphorylation of NF accumulations found in neurodegeneration could be attributable to either deregulation of proline-directed Ser/Thr kinase(s) activity or downregulation of protein phosphatase(s) activity. In this study, we found that protein phosphatase 2A (PP2A) expression is high in neuronal cell bodies and that inhibition of PP2A activity by okadaic acid (OA), microcystin LR (mLR), or fostriecin (Fos) leads to perikaryal hyperphosphorylation of NF. Peptidyl-prolyl isomerase Pin1 inhibits the dephosphorylation of NF by PP2A in vitro. In cortical neurons, Pin1 modulates the topographic phosphorylation of the proline-directed Ser/Thr residues within the tail domain of NF proteins by inhibiting the dephosphorylation by PP2A. Inhibition of Pin1 inhibits OA-induced aberrant perikaryal phosphorylation of NF. Treatment of cortical neurons with OA or Fos prevents the general anterograde transport of transfected green fluorescent protein-high-molecular-mass (NF-H) into axons caused by hyperphosphorylation of NF-H, and inhibition of Pin1 rescues this effect. Furthermore, inhibition of Pin1 inhibits the OA- or Fos-induced neuronal apoptosis. We show that OA-induced hyperphosphorylation of NF is a consequence of dephosphorylation of NF and is independent of c-Jun N-terminal protein kinase, extracellular signal-regulated kinase, and cyclin-dependent kinase-5 pathways. This study highlights a novel signaling role of PP2A by Pin1 and implicates Pin1 as a therapeutic target to reduce aberrant phosphorylation of NF proteins in neurodegenerative disorders such as AD, PD, and ALS.
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PMID:Peptidyl-prolyl isomerase 1 regulates protein phosphatase 2A-mediated topographic phosphorylation of neurofilament proteins. 1994 Jan 83

The mammalian family of mitogen-activated protein kinases (MAPKs) includes extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK), with each MAPK signaling pathway consisting of at least three components, a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS, whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion. In this review, we summarize recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS.
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PMID:Pathological roles of MAPK signaling pathways in human diseases. 2007 33


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