Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Controversial debates still remain around the nature of the etiologic agent responsible for Amyotrophic lateral sclerosis/Parkinson dementia complex (ALS/PDC) whose incidence is unusually high among the population of the pacific island of Guam. It has been hypothesized that the neurotoxin beta-N-methylamino-L-alanine (L-BMAA) produced by cyanobacteria in the roots of Cycas Circinalis seeds might trigger ALS/PDC. Frequently observed in patients with ALS/PDC, retinopathy is one of the clinical features of the disease. The effect of the L-BMAA on cell viability was examined in vivo by measuring the electrophysiological activity of the mouse retinal neurons by electroretinography recordings. Intra-ocular injections of L-BMAA selectively reduced the b-wave amplitude, without affecting neither the a-wave amplitude nor the a- and b-latencies. The cell death of retinal cells was evidenced by histology on retina sections, caspase 3 activation, incorporation of propidium iodide and production of reactive oxygen species. Co-injection with the specific NMDA antagonist, MK-801, significantly protected the retinal neurons from L-BMAA/NMDA-induced apoptosis. We provide evidence that L-BMAA induced neuronal cell death in vivo supporting a direct causal link between L-BMAA and neuronal damages.
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PMID:beta-N-methylamino-L-alanine induced in vivo retinal cell death. 1930 37

Increasing evidence indicates that the accumulation and aggregation of mutant Cu,Zn superoxide dismutase (mutSOD1) in spinal cord mitochondria is implicated in the pathogenesis of familial amyotrophic lateral sclerosis (FALS). Although the mechanisms underlying this effect are only partially understood, a deficit in the import mechanism of mutSOD1 and/or in its folding and maturation inside mitochondria is likely involved. To investigate this issue, we overexpressed mitochondria-targeted wild-type and mutSOD1s in neuronal cell lines. Mitochondria-targeted G93A mutSOD1 induces a significant impairment of mitochondrial morphology and metabolism, resulting in caspase-3 activation and cell death. These effects are paralleled by the formation of disulfide-linked, insoluble oligomers of mutSOD1 inside mitochondria. Overexpression of the copper chaperone for SOD1 (CCS) improves the solubility of cytosolic mutSOD1s, but has no effect or even worsens the insolubility of mitochondria-targeted G93A mutSOD1, indicating that CCS may increase the availability of an aggregating form of mutSOD1. Interestingly, prevention of the formation of such aggregates by removal of disulfide-bonded cysteines counteracts the effects produced by mutSOD1 accumulated inside mitochondria. Overall, our results demonstrate for the first time that aggregation of mutSOD1s into mitochondria is important for mutSOD1 to induce damage, although other forms of misfolded SOD1s might be involved.
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PMID:Oligomerization of mutant SOD1 in mitochondria of motoneuronal cells drives mitochondrial damage and cell toxicity. 1934 52

The accumulation of reactive microglia in the degenerating areas of amyotrophic lateral sclerosis (ALS) tissue is a key cellular event creating a chronic inflammatory environment that results in motoneuron death. We have developed a new culture system that consists in rat spinal cord embryonic explants in which motoneurons migrate outside the explant, growing as a monolayer in the presence of glial cells. The proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) have been proposed to be involved in ALS-linked microglial activation. In our explants, the combined exposure to these cytokines resulted in an increased expression of the pro-oxidative enzymes inducible nitric oxide synthase (iNOS), the catalytic subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) and cyclooxygenase-2 (COX-2), as compared to each cytokine alone. This effect was related to their cooperation in the activation of the transcription factor nuclear factor kappa B (NF-kappaB). TNF-alpha and IFN-gamma also cooperated to promote protein oxidation and nitration, thus increasing the percentage of motoneurons immunoreactive for nitrotyrosine. Apoptotic motoneuron death, measured through annexin V-Cy3 and active caspase-3 immunoreactivities, was also found cooperatively induced by TNF-alpha and IFN-gamma. Interestingly, these cytokines did not affect the viability of purified spinal cord motoneurons in the absence of glial cells. It is proposed that the proinflammatory cytokines TNF-alpha and IFN-gamma have cooperative/complementary roles in inflammation-induced motoneuron death.
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PMID:Tumor necrosis factor alpha and interferon gamma cooperatively induce oxidative stress and motoneuron death in rat spinal cord embryonic explants. 1947 38

TAR DNA binding protein (TDP-43) mislocalization has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We have recently reported that TDP-43 and PGRN expression is altered in response to axotomy in C57BL6 mice and that normal expression is restored following recovery. We have performed axotomies in two different presymptomatic models of motor neuron degeneration, low molecular weight neurofilament knockout (NFL(-/-)) mice and mutant SOD1(G93A) transgenic (mtSOD1(G93A)) mice aged 6 weeks, and observed TDP-43 and PGRN expression patterns in axotomized spinal motor neurons over 28 days. In contrast to both C57BL6 mice and mtSOD1(G93A) mice, behavioural deficits in NFL(-/-) mice were sustained. We did not observe differences in TDP-43 or PGRN expression between C57BL6 mice and mtSOD1(G93A) mice throughout the observation period. However, compared to C57BL6 mice and mtSOD1(G93A) mice, NFL(-/-) mice exhibited late upregulation of cytosolic TDP-43 expression and persistent downregulation of neuronal PGRN expression accompanied by caspase 3 activation on post-injury day 28. By post-injury day 42, no cytosolic TDP-43-positive neurons remained in NFL(-/-) mice, suggesting that they had undergone apoptotic cell death. These findings suggest that whereas TDP-43 expression is normally upregulated transiently following axotomy, in the absence of NFL this response is delayed and associated with caspase 3 activation and neuronal death. These results further support that TDP-43 is involved in neurofilament mRNA metabolism and transport, and provide insight into the pathogenesis of motor neuron death in ALS in which NFL mRNA levels are selectively suppressed.
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PMID:Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-/- mice: support for a role for TDP-43 in the physiological response to neuronal injury. 1961 16

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective loss of motor neurons (MNs). Twenty percent of familial ALS cases are associated with mutations in Cu(2+)/Zn(2+) superoxide dismutase (SOD1). To specifically understand the cellular mechanisms underlying mutant SOD1 toxicity, we have established an in vitro model of ALS using rat primary MN cultures transfected with an adenoviral vector encoding a mutant SOD1, G93A-SOD1. Transfected cells undergo axonal degeneration and alterations in biochemical responses characteristic of cell death such as activation of caspase-3. Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can increase axonal outgrowth, block neuronal apoptosis, and promote neurogenesis. Decreased VEGF gene expression in mice results in a phenotype similar to that seen in patients with ALS, thus linking loss of VEGF to the pathogenesis of MN degeneration. Decreased neurotrophic signals prior to and during disease progression may increase MN susceptibility to mutant SOD1-induced toxicity. In this study, we demonstrate a decrease in VEGF and VEGFR2 levels in the spinal cord of G93A-SOD1 ALS mice. Furthermore, in isolated MN cultures, VEGF alleviates the effects of G93A-SOD1 toxicity and neuroprotection involves phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Overall, these studies validate the usefulness of VEGF as a potential therapeutic factor for the treatment of ALS and give valuable insight into the responsible signaling pathways and mechanisms involved.
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PMID:Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration. 1967 55

Oxidative stress leading to lipid peroxidation is a problem in neurodegenerative diseases, because the brain is rich in polyunsaturated fatty acids and low in endogenous antioxidants. One of the most toxic byproducts of lipid peroxidation, 4-hydroxynonenal (HNE), is implicated in oxidative stress-induced damage in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). In this study, the human neuroblastoma cell line SH-SY5Y was used to test the protective effects of increasing the detoxification of HNE by overexpressing the HNE-detoxifying enzyme aldehyde dehydrogenase 1A1 (ALDH1). Overexpression of ALDH1 in the SH-SY5Y cells acts to reduce production of protein-HNE adducts and activation of caspase-3. Our data suggest that detoxification of HNE could be therapeutic in preventing some of the toxic disruptions of the brain's redox systems found in many neurodegenerative diseases.
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PMID:Overexpression of aldehyde dehydrogenase 1A1 reduces oxidation-induced toxicity in SH-SY5Y neuroblastoma cells. 1977 75

TAR DNA-binding protein-43 (TDP-43) has been recently identified as a major component of the ubiquitinated inclusions found in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis, diseases that are collectively termed TDP-43 proteinopathies. Several amyotrophic lateral sclerosis-linked mutations of the TDP-43 gene have also been identified; however, the precise molecular mechanisms underlying the neurodegeneration remain unclear. To investigate the biochemical characteristics of TDP-43, we examined truncation, isoforms, and cytoplasmic inclusion (foci) formation using TDP-43-expressing cells. Under apoptosis, caspase-3 generates two 35-kDa (p35f) and 25-kDa (p25f) fragments. However, in caspase-3(-/-) cells, novel caspase-3-independent isoforms of these two variants (p35iso and p25iso) were also detected under normal conditions. With a deletion mutant series, the critical domains for generating both isoforms were determined and applied to in vitro transcription/translation, revealing alternate in-frame translation start sites downstream of the natural initiation codon. Subcellular localization analysis indicated that p35 (p35f and p35iso) expression leads to the formation of stress granules, cellular structures that package mRNA and RNA-binding proteins during cell stress. After applying proteasome inhibitors, aggresomes, which are aggregates of misfolded proteins, were formed in the cytoplasm of cells expressing p35. Collectively, this study demonstrates that the 35-kDa isoforms of TDP-43 assemble in stress granules, suggesting that TDP-43 plays an important role in translation, stability, and metabolism of mRNA. Our findings provide new biological and pathological insight into the development of TDP-43 proteinopathies.
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PMID:Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43. 1988 43

Impaired glutamate uptake function of astrocytes associated with accumulation of extracellular glutamate is a well-documented feature of amyotrophic lateral sclerosis (ALS). Enhancing the uptake function of astrocytic glutamate transport 1 (GLT1) may be a potential treatment for this disease. Human adipose-derived stem cells (hADSCs) are capable of secreting a large number of cytokines which exhibit diverse pharmacological effects. Therefore, we investigate the influence of the soluble factors released by hADSCs on the GLT1 in primary astrocytes cultured from SOD1(G93A) mice, a widely studied mutant human SOD1 transgenic model of ALS. Our data indicate that soluble factors from hADSCs significantly upregulate the expression of GLT1 in SOD1(G93A)-bearing astrocytes, which result in enhanced glutamate uptake function. The upregulation of GLT1 is accompanied by the inhibition of caspase-3 activation in mutant astrocytes. In addition, we find that hADSCs cocultured with SOD1(G93A)-bearing astrocytes produce more VEGF, HGF and IGF-1, which are reported to have neuroprotective effects. Our results suggest that hADSCs may be a potential candidate in cellular therapy for ALS.
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PMID:Human adipose-derived stem cells enhance the glutamate uptake function of GLT1 in SOD1(G93A)-bearing astrocytes. 2015 7

The hyperphosphorylation and proteolytic modification of the TAR DNA binding protein-43 (TDP-43) is a key finding in a number of neurodegenerative diseases including frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U), amyotrophic lateral sclerosis (ALS), and most recently Alzheimer's disease (AD). To examine whether proteolytic modifications of TDP-43 is a relevant finding in Pick's disease, we utilized a novel site-directed caspase-cleavage antibody based upon a known caspase-3 cleavage consensus site within TDP-43 at position 219. Application of this antibody, termed TDP caspase-cleavage product (TDPccp) to postmortem Pick's disease brain sections revealed the presence of caspase-cleaved TDP-43 in Pick and Hirano bodies predominantly within region CA1 of the hippocampus. Co-localization of TDPccp with PHF-1, a general marker for Pick bodies, as well as with an antibody to caspase-cleaved tau (TauC3) was evident within the hippocampus. A semi-quantitative analysis indicated that approximately 21% and 79% of the Pick bodies identified in area CA1 contained caspase-cleaved TDP-43 or caspase-cleaved tau, respectively. Of interest was the lack of co-localization of TDPccp with PHF-1 in Pick bodies within the dentate gyrus. Collectively, these data have identified modified TDP-43 as a component of Pick and Hirano bodies that is restricted to area CA1 in Pick's disease. The relative paucity of caspase-cleaved TDP-43 found within Pick bodies in comparison to caspase-cleaved tau suggests that TDP-43 and its modification by caspases is most likely not a contributing factor leading to Pick body formation.
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PMID:Caspase-cleaved TAR DNA-binding protein-43 in Pick's disease. 2041 Oct 29

Mutations in the superoxide dismutase 1 (SOD1) gene are linked to glutamate excitotoxicity in familial amyotrophic lateral sclerosis (fALS), but the underlying mechanism remains unclear. We investigated whether nuclear factor-kappaB (NF-kappaB) activation is involved in glutamate excitotoxicity by using motor neuron-neuroblastoma hybrid cells that expressed a mutant (G93A) SOD1 (mtSOD1) or wild-type SOD1 (wtSOD1). MtSOD1 cells were more vulnerable to glutamate excitotoxicity than wtSOD1 cells and showed higher NF-kappaB activity, higher nuclear cRel expression, and lower nuclear RelA expression under basal conditions. Glutamate treatment increased NF-kappaB activation along with nuclear expressions of RelA and cRel in wtSOD1 cells but induced only weak nuclear RelA expression in mtSOD1 cells. Suppression of NF-kappaB activation using transfection of the superrepressive mutant form of IkappaBalpha (mIkappaBalpha) inhibited nuclear RelA expression in both types of SOD1 cells, which increased glutamate excitotoxicity in wtSOD1 cells but not in mtSOD1 cells. Furthermore, immunohistochemistry confirmed stronger RelA immunoreactivity in the nuclei of motor neurons of spinal cord in wild-type SOD1 transgenic mice than in those in SOD1 G93A transgenic mice. In addition, we found that glutamate treatment decreased XIAP expression and increased caspase-3 activity in mtSOD1 cells and mIkappaBalpha-overexpressing wtSOD1 cells. Our results suggest that glutamate excitotoxicity in motor neurons of SOD1-linked fALS is attributable, at least in part, to the impairment of IkappaBalpha-dependent RelA activation and subsequent apoptosis mediated by XIAP inhibition and caspase-3 activation.
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PMID:Impairment of nuclear factor-kappaB activation increased glutamate excitotoxicity in a motoneuron-neuroblastoma hybrid cell line expressing mutant (G93A) Cu/Zn-superoxide dismutase. 2062 31


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