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)

Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.
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PMID:The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. 1971 Mar 15

Oxidative stress induced by reactive oxygen species (ROS) is strongly associated with the pathogenesis of various neurodegenerative disorders, including Alzheimer's disease. We investigated the possible combined effects of gallic acid and resveratrol, which are major antioxidants present in fruit, including grapes, on PC12 rat pheochromocytoma (PC12) cell death. Gallic acid did not protect against H(2)O(2)-induced PC12 cell death; it reduced the viability of PC12 cells in a dose-dependent manner. Gallic acid also induced cleavage of poly (ADP-ribose) polymerase, which is strongly related to apoptosis in neurons. Gallic acid induced the phosphorylation of c-Jun N-terminal protein kinase (JNK) and the downregulation of Bcl-2 in PC12 cells. Treatment of PC12 cells with resveratrol increased their viability in a dose-dependent manner by blocking the activation of JNK and the downregulation of Bcl-2. Furthermore, gallic acid led to a progressive reduction in the viability of vector-transfected PC12 cells, which was delayed in PC12 cells that overexpressed Bcl-2. The JNK inhibitor SP600125 protected against gallic acid-induced PC12 cell death. Collectively, these findings suggest that the combined effects of dietary phenolic phytochemicals on oxidative neuronal cell death and antioxidants differ in ROS-mediated neuronal cell death.
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PMID:Gallic acid induces neuronal cell death through activation of c-Jun N-terminal kinase and downregulation of Bcl-2. 1972 98

Significant increase in JNK, c-Jun, and Cdk5 activities are reported in Alzheimer's disease (AD). Inhibition of c-Jun prevents neuronal cell death in in vivo AD models, highlighting it as a major JNK effector. Both JNK and Cdk5 promote neurodegeneration upon deregulation; however, Cdk5 has not been mechanistically linked to JNK or c-Jun. This study presents the first mechanism showing Cdk5 as a major regulator of the JNK cascade. Deregulated Cdk5 induces biphasic activation of JNK pathway. The first phase revealed c-Jun as a direct substrate of Cdk5, whose activation is independent of reactive oxygen species (ROS) and JNK. In the second phase, Cdk5 activates c-Jun via ROS-mediated activation of JNK. Rapid c-Jun activation is supported by in vivo data showing c-Jun phosphorylation in cerebral cortex upon p25 induction in transgenic mice. Cdk5-mediated biphasic activation of c-Jun highlights c-Jun, rather than JNK, as an important therapeutic target, which was confirmed in neuronal cells. Finally, Cdk5 inhibition endows superior protection against neurotoxicity, suggesting that Cdk5 is a preferable therapeutic target for AD relative to JNK and c-Jun.
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PMID:Direct and indirect roles of cyclin-dependent kinase 5 as an upstream regulator in the c-Jun NH2-terminal kinase cascade: relevance to neurotoxic insults in Alzheimer's disease. 1977 50

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

The 5-HT(6) receptor (5-HT(6)R) is one of the most recently cloned serotonin receptors, and it plays important roles in Alzheimer disease, depression, and learning and memory disorders. However, unlike the other serotonin receptors, the cellular mechanisms of 5-HT(6)R are poorly elucidated relative to its significance in human brain diseases. Here, using a yeast two-hybrid assay, we found that the human 5-HT(6)R interacts with Jun activation domain-binding protein-1 (Jab1). We also confirmed a physical interaction between 5-HT(6)R and Jab1 using glutathione S-transferase pulldown, fluorescence resonance energy transfer, co-immunoprecipitation, and immunocyto(histo)chemistry assays. The manipulation of Jab1 expression using Jab1 small interference RNA decreased 5-HT(6)R-mediated activity and cell membrane expression of 5-HT(6)R, whereas overexpression of Jab1 produced no significant effect. In addition, we demonstrated that the activation of 5-HT(6)R induced the translocation of Jab1 into the nucleus and increased c-Jun phosphorylation and the interaction between Jab1 and c-Jun. Furthermore, we found that 5-HT(6)R and Jab1 were up-regulated in middle cerebral artery occlusion-induced focal cerebral ischemic rats and in cultured cells exposed to hypoxic insults, suggesting possible protective roles for 5-HT(6)R and Jab1. These findings suggest that Jab1 provides a novel signal transduction pathway for 5-HT(6)R and may play an important role in 5-HT(6)R-mediated behavior changes in the brain.
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PMID:Physical interaction of Jab1 with human serotonin 6 G-protein-coupled receptor and their possible roles in cell survival. 2009 69

Pin1 [Protein Interacting with NIMA (never in mitosis A)] is a peptidyl prolyl cis-trans isomerase that isomerizes phospho-Serine/Threonine-Proline [p(S/T)-P] motifs of its target proteins. Pin1 functions in concert with proline directed kinases such as cyclin-dependent protein kinases, extracellular signal-regulated kinases, and c-Jun N- terminal kinase, and protein phosphatases such as protein phosphatase 2A (PP2A) and PP2B, in the regulation of a wide range of cellular processes including cell division, DNA damage response, and gene transcription, and in susceptibility to cancer and neurodegenerative diseases. This review focuses on the roles of Pin1 in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Frontotemporal dementia associated with parkinsonism linked to chromosome 17. Pin1 interacts with neuronal cytoskeletal proteins such as tau, amyloid-beta protein precursor, alpha-synuclein, and neurofilaments, often in association with phosphorylation events that influence their functions in the neuronal cytoskeleton. Overexpression of Pin1 reduces WT tau stability but increases P301L mutant tau stability. Pin1 associates with neurofilament H (NF-H) and modulates excitotoxic and oxidative stress induced perikaryal phosphorylation of NF-H. Pin1 mediates the neural specific apoptosis machinery. The specific inhibitors of Pin1 may have potential therapeutic implications in neurodegeneration.
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PMID:Phosphorylation-specific peptidyl-prolyl isomerization of neuronal cytoskeletal proteins by Pin1: implications for therapeutics in neurodegeneration. 2011 May 89

Cyclin-dependent kinase (Cdk) 5 and p38 activities are significantly increased in Alzheimer's Disease (AD). Both p38 and Cdk5 promote neurodegeneration upon deregulation. However, to date the mechanistic link between Cdk5 and p38 remains unclear. This study presents the first mechanism showing Cdk5 as a major regulator of p38 cascade in neurons and in transgenic mouse model of AD. Using beta-amyloid and glutamate as the neurotoxic stimuli, our results show that deregulated Cdk5 induces p38 activation by increasing reactive oxygen species (ROS) in neuronal cells and in primary cortical neurons. Elimination of ROS inhibits p38 activation, revealing ROS as major stimuli of the p38 cascade. Importantly, Cdk5-mediated p38 activation increases c-Jun expression, thereby revealing a mechanistic link between deregulated Cdk5 and c-Jun level in AD brains. c-Jun is over-expressed in AD, and is believed to contribute significantly to neurodegeneration. Based on the proposed mechanism, Cdk5 inhibition is more neuroprotective relative to p38 and c-Jun, suggesting that Cdk5 is an upstream regulator of neurodegenerative pathways triggered by p38 and a preferable therapeutic target for AD.
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PMID:Cdk5 is a major regulator of p38 cascade: relevance to neurotoxicity in Alzheimer's disease. 2034 61

Neurodegenerative disorders, such as Alzheimer's disease (AD), is associated with the loss of neuronal cells, and it has been suggested that apoptosis is a crucial pathway in neuronal loss in AD patients. Recent evidence suggests that amyloid beta peptide (Abeta) induces neuronal apoptosis in the brain and in primary neuronal cultures. In this study, we investigated the impact of beta-asarone against the apoptosis induced by Abeta in rat hippocampus. The results showed that intrahippocampal injections of Abeta (1-42) caused apoptosis in rat hippocampus. Oral administration of beta-asarone (12.5, 25, or 50 mg/kg) for 28 d reverse the increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus tissue. Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in AD. Therefore, we investigated nuclear translocation of apoptosis induction factors. Our results showed that beta-asarone afforded a beneficial inhibition on both mRNA and protein expression of Bad, Bax, and cleavage of caspases 9 in rat hippocampus following intrahippocampal injections of Abeta (1-42). Our further investigation revealed that ASK1, p-MKK7, and p-c-Jun were significantly decreased after beta-asarone treatment, implicating that the modulation of ASK1/c-JNK-mediated intracellular signaling cascades might be involved in therapeutic effect of beta-asarone against Abeta toxicity. Taken together, these results suggest that beta-asarone may be a potential candidate for development as a therapeutic agent for AD.
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PMID:Beta-asarone attenuates neuronal apoptosis induced by Beta amyloid in rat hippocampus. 2046 Aug 73

Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson disease, and cerebral ischemia. In this study, we investigated the effects of apigenin on ER stress-induced apoptosis in murine HT22 hippocampal neuronal cells. Apigenin reduced apoptotic cell death of HT22 cells induced by thapsigargin (TG) and brefeldin A (BFA), two representative ER stress inducers. Consistent with these findings, apigenin blocked TG- and BFA-induced activation of caspase-12 and -3 and cleavage of poly (ADP-ribose) polymerase. Apigenin also reduced the TG- and BFA-induced expression of ER stress-associated proteins, including C/EBP homologous protein (CHOP), glucose-regulated protein (GRP) 78 and GRP94, the cleavage of activating transcription factor 6alpha, the phosphorylation of eukaryotic initiation factor 2alpha and inositol-requiring enzyme 1alpha, and the activation of mitogen-activated protein kinases, such as p38, c-Jun NH(2)-terminal kinase, and extracellular-regulated kinase. We also found that antioxidants such as N-acetylcysteine and glutathione blocked TG- and BFA-induced cell death and the expression of CHOP and GRP78. These results suggest that TG- and BFA-induced reactive oxygen species (ROS) accumulation plays an important role in ER stress-induced apoptosis. Apigenin also reduced TG- and BFA-induced ROS accumulation, suggesting that it exerts an antioxidant effect against ER stress inducers. Moreover, apigenin recovered TG- and BFA-induced reduction of the mitochondrial membrane potential in HT22 cells. Taken together, these results suggest that apigenin could protect HT22 neuronal cells against ER stress-induced apoptosis by reducing CHOP induction as well as ROS accumulation and mitochondrial damage.
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PMID:Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. 3110 77


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