Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal models of motor neurone disease (MND) are being increasingly used for screening molecules with clinical potential. A number of different treatments to decrease the progression of neuronal cell loss have been proposed; these include: Bcl-2 (B-cell leukaemia oncogene-2), neurotrophic factors, glutamate receptor inhibitors and Ca2+ channel antagonists. In this review Yves Sagot, Richard Vejsada and Ann C. Kato focus on the effects of neurotrophic factors and Bcl-2, both of which have been shown to prevent cell death in various experimental paradigms. Studies performed in animal models of MND have confirmed the potential of these molecules to support motoneurone survival. Some of them have been shown to act in synergy and these results are discussed in the context of molecular mechanisms leading to collaborative and synergistic activities, and also with respect to presumptive subpopulations of motoneurones, which express diverse receptors for neurotrophic factors. Finally, the current status of clinical trials for amyotrophic lateral sclerosis using neurotrophic factors will be discussed, as well as recent reports that neurotrophic factors can exert adverse effects on neuronal survival.
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PMID:Clinical and molecular aspects of motoneurone diseases: animal models, neurotrophic factors and Bcl-2 oncoprotein. 934 52

Bcl-2 family proteins are principal regulators of cell death during normal development as well as in many disease states. Differentiated cerebellar granule neurons are protected from apoptosis by depolarizing concentrations of potassium. Further, these cells acquire resistance to glutamate-mediated excitotoxicity when pre-exposed to subtoxic concentrations of the glutamate receptor agonist, N-methyl-D-aspartate. Here, we report that the expression of bcl-2, bcl-xL, bcl-xS, bax and bad mRNA as well as of Bcl-2, Bax, Bcl-XL, Bcl-XS and Bag-1 proteins is not modulated in these two paradigms of neuronal cell death. However, mitochondrial release of cytochrome c, which is thought to be controlled by Bcl-2 family proteins, is detected 5 h after switching the neurons to low potassium conditions. Thus, there appears to be regulation of Bcl-2 family protein bioactivity in the absence of altered protein expression during potassium deprivation-induced apoptosis of cerebellar granule neurons.
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PMID:Potassium deprivation-induced apoptosis of cerebellar granule neurons: cytochrome c release in the absence of altered expression of Bcl-2 family proteins. 969 46

Lurcher is a gain-of-function mutation in the delta2 glutamate receptor gene (Grid2) that turns the receptor into a leaky ion channel. The expression of the Lurcher gene in heterozygous (Grid2(Lc/+)) mutants induces the death of almost all Purkinje cells starting from the second postnatal week. Ninety percent of the granule cells and 60-75% of the inferior olivary neurons die because of the loss of their target neurons, the Purkinje cells. The apoptotic nature of the neurodegeneration has been demonstrated previously by the presence of activated caspase-3 and DNA fragmentation. Bax, a pro-apoptotic gene of the Bcl-2 family, has been shown to be involved in developmental neuronal death. To study the role of Bax in Grid2(Lc/+) neurodegeneration, double mutants with Grid2(Lc/)+ mice and Bax knock-out mice (Bax-/-) were generated. Bax deletion had no effect on the death of Purkinje cells and inferior olivary neurons, although a temporary rescue of some Purkinje cells could be detected in P15 Grid2(Lc/)+;Bax-/- animals. From postnatal day 15 (P15) to P60, the number of granule cells in Grid2(Lc/)+;Bax-/-mice did not significantly change and was significantly increased compared with the number found in Grid2(Lc/)+;Bax+/+ mice. Granule cell number in P60 Grid2(Lc/)+;Bax-/- mice corresponded to 70% of the number found in wild-type mice. Our results show that Bax inactivation in Grid2(Lc/+) mice does not rescue intrinsic Purkinje cell death or the target-related cell death of olivary neurons, but Bax inactivation does inhibit persistently target-related cell death in cerebellar granule cells.
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PMID:Bax inactivation in lurcher mutants rescues cerebellar granule cells but not purkinje cells or inferior olivary neurons. 1088 18

Integrins are integral membrane proteins that mediate adhesive interactions of cells with the extracellular matrix and with other cells. Integrin engagement results in activation of intracellular signaling cascades that effect several different cellular responses including motility, proliferation and survival. Although integrins are known to provide cell survival signaling in various types of non-neuronal cells, the possibility that integrins modulate neuron survival has not been explored. We now report data demonstrating a neuroprotective function of integrins in embryonic hippocampal neurons. Neurons grown on laminin, an integrin ligand, exhibit increased resistance to glutamate-induced apoptosis compared with neurons grown on polylysine. Neurons expressed integrin beta1 and treatment of cultures with an antibody against integrin beta1 abolished the protective effect of laminin. Neurons maintained on laminin exhibited a sustained activation of the Akt signaling pathway demonstrated in immunoblot analyses using an antibody that selectively recognizes phosphorylated Akt. The neuroprotective effect of integrin engagement by laminin was mimicked by an IKLLI-containing integrin-binding peptide and was abolished by treatment of neurons with the PI3 kinase inhibitor wortmanin. Levels of the anti-apoptotic protein Bcl-2 were increased in neurons grown on laminin and decreased by wortmanin, suggesting a mechanism for the neuroprotective effect of integrin-mediated signaling. The ability of integrin-mediated signaling to prevent glutamate-induced apoptosis suggests a mechanism whereby neuron-substrate interactions can promote neuron survival under conditions of glutamate receptor overactivation.
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PMID:Integrin signaling via the PI3-kinase-Akt pathway increases neuronal resistance to glutamate-induced apoptosis. 1123 33

The NMDA-type glutamate receptor is a predominant mediator of excitotoxicity in the immature brain due to overexpression of the receptor in the developing brain. Within the development period however, the extent of NMDA receptor mediated processes including hypoxia-induced excitotoxicity may depend on the ontogeny of the NMDA receptor recognition and modulation sites, and subunits leading to altered function of the ion-channel comples. The function of the receptor may be modified by intracellular mechanisms such as phosphorylation/dephosphorylation, nitration, and generation of free radicals including nitric oxide. The susceptibility of the developing brain to hypoxia depends on several factors: the lipid composition of the brain cell membrane; the rate of membrane lipid peroxidation and the status of anti-oxidant defenses; the development and modulation of the NMDA receptor sites; the intracellular Ca(2+) influx mechanisms; expression of apoptotic and antiapoptotic genes such as Bax and Bcl-2; and the activation of initiator caspases and caspase-3, the "executioner" of cell death. The developmental status of these cellular mechanisms and their response to hypoxia determine the fate of the hypoxic cell in the developing brain in the fetus and the newborn.
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PMID:NMDA receptor and neonatal hypoxic brain injury. 1175 18

Neuronal apoptosis within the central nervous system (CNS) is a characteristic feature of AIDS dementia, and it represents a common mechanism of neuronal death induced by neurotoxins (e.g., glutamate) released from human immunodeficiency virus (HIV)-infected macrophages (HIV/macrophage-induced neurotoxicity). Neuronal apoptosis may result from activation of the intrinsic (mitochondrial/bcl-2 regulated) or extrinsic (death receptor) pathways, although which pathway predominates in CNS HIV infection is unknown. Apoptosis initiated by the intrinsic pathway is typically blocked by antiapoptosis Bcl-2 family proteins, such as Bcl-2 and Bcl-xL, but whether these can block HIV/macrophage-induced neuronal apoptosis is unknown. To determine the potential role of the Bcl-2 family in HIV/macrophage-induced neuronal apoptosis, we developed a unique in vitro model, utilizing the NT2 neuronal cell line, primary astrocytes and macrophages, and primary CNS HIV type 1 (HIV-1) isolates. We validated our model by demonstrating that NT2.N neurons are protected against HIV-infected macrophages by N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, similar to effects seen in primary neurons. We then established stable NT2.N neuronal lines that overexpress Bcl-2 or Bcl-xL (NT2.N/bcl-2 and NT2.N/bcl-xL, respectively) and determined their sensitivity to macrophages infected with primary R5, X4, and R5/X4 HIV-1 isolates. We found that NT2.N/bcl-2 and NT2.N/bcl-xL neurons were resistant to apoptosis induced by either R5, X4, or R5/X4 isolates and that resistance was abrogated by a Bcl-2 antagonist. Thus, the NMDA receptor/bcl-2-regulated apoptotic pathway contributes significantly to HIV/macrophage-induced neuronal apoptosis, and Bcl-2 family proteins protect neurons against the spectrum of primary HIV-1 isolates. Modulation of bcl-2 gene expression may therefore offer adjunctive neuroprotection against development of AIDS dementia.
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PMID:Development of a human neuronal cell model for human immunodeficiency virus (HIV)-infected macrophage-induced neurotoxicity: apoptosis induced by HIV type 1 primary isolates and evidence for involvement of the Bcl-2/Bcl-xL-sensitive intrinsic apoptosis pathway. 1218 23

Mitochondrial permeability transition (MPT) is a nonselective inner membrane permeabilization that contributes to neuronal cell death under circumstances such as brain trauma, ischemia, and hypoglycemia. Here we study the participation of MPT and the Bcl-2-sensitive apoptotic cell death pathway in glutamate receptor-mediated excitotoxicity. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neurodegeneration in both rats and mice. Interestingly, transgenic mice overexpressing human Bcl-2 and rats systemically treated with cyclosporin A did not exhibit reduced sensitivity to quinolinic acid-induced striatal toxicity. Both Bcl-2 and cyclosporin A are inhibitors of MPT; in addition Bcl-2 also inhibits apoptotic stimuli-mediated release of mitochondrial apoptogenic factors. Isolated brain mitochondria from cyclosporin A-treated rats showed resistance to Ca(2+)-induced dissipation of the membrane potential, indicating protection against MPT. We conclude that quinolinic acid-mediated striatal excitotoxicity is not dependent on MPT and Bcl-2-sensitive apoptotic cell death pathways.
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PMID:Cyclosporin A and Bcl-2 do not inhibit quinolinic acid-induced striatal excitotoxicity in rodents. 1455 83

Lurcher (lc) mice have a semi-dominant mutation in the gene encoding the delta2 glutamate receptor (GRID2). The resulting constitutive activity of this receptor in heterozygous +/lc (grid(+/lc)) and homozygous (grid(lc/lc)) mice leads to the death of all cerebellar Purkinje cells and most afferent granule neurons. Some studies have indicated that the death of Purkinje cells occurs by apoptosis, and the secondary loss of granule neurons has been shown to require the pro-apoptotic Bcl-2 family member Bax. The BH3-only protein Bim has been shown to contribute to cytokine withdrawal-induced apoptosis of sympathetic neurons and to be responsible for the kidney degeneration in mice lacking the pro-survival protein Bcl-2. Because Bim is expressed strongly in cerebellar Purkinje cells, we have examined whether it has a role in their death in mutant Lurcher mice. Our studies show that Bim deficiency does not modify the Lurcher phenotype, ruling out an indispensable role for Bim in this neurodegenerative disease.
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PMID:Loss of pro-apoptotic BH3-only Bcl-2 family member Bim does not protect mutant Lurcher mice from neurodegeneration. 1463 29

Nutrient deprivation during ischemia leads to severe insult to neurons causing widespread excitotoxic damage in specific brain regions such as the hippocampus. One possible strategy for preventing neurodegeneration is to express therapeutic proteins in the brain to protect against excitotoxicity. We investigated the utility of equine infectious anemia virus (EIAV)-based vectors as genetic tools for delivery of therapeutic proteins in an in vivo excitotoxicity model. The efficacy of these vectors at preventing cellular loss in target brain areas following excitotoxic insult was also assessed. EIAV vectors generated to overexpress the human antiapoptotic Bcl-2 or growth factor glial-derived neurotrophic factor (GDNF) genes protected against glutamate-induced toxicity in cultured hippocampal neurons. In an in vivo excitotoxicity model, adult Wistar rats received a unilateral dose of the glutamate receptor agonist N-methyl-D-aspartate to the hippocampus that induced a large lesion in the CA1 region. Neuronal loss could not be protected by prior transduction of a control vector expressing beta-galactosidase. In contrast, EIAV-mediated expression of Bcl-2 and GDNF significantly reduced lesion size thus protecting the hippocampus from excitotoxic damage. These results demonstrate that EIAV vectors can be effectively used to deliver putative neuroprotective genes to target brain areas and prevent cellular loss in the event of a neurological insult. Therefore these lentiviral vectors provide potential therapeutic tools for use in cases of acute neurotrauma such as cerebral ischemia.
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PMID:Lentiviral-mediated delivery of Bcl-2 or GDNF protects against excitotoxicity in the rat hippocampus. 1558 9

Alphaviruses are mosquito-borne, enveloped, plus-strand RNA viruses that cause a spectrum of diseases in humans that include fever, rash, arthritis, meningitis, and encephalomyelitis. Sindbis virus (SINV) is the prototype alphavirus, causes encephalomyelitis in mice, and provides a model system for studying the pathogenesis of alphavirus-induced neurological disease. Major target cells for SINV infection in the central nervous system (CNS) are neurons, and both host and viral factors determine the fate of infected neurons. Young animals are most susceptible to fatal disease. This correlates with the ability of SINV to induce apoptosis in immature neurons. In vitro, apoptotic death of neuroblastoma cells can be induced by fusion of the virus envelope with the endosomal membrane and does not require infectious virus. This fusion process activates acid sphingomyelinase that cleaves sphingomyelin to release ceramide, an initiator of apoptosis. Within an hour, poly(ADP-ribose) polymerase is activated, and this is followed by release of cytochrome c and activation of effector caspases. SINV-induced cell death can be delayed or prevented by treatment with antioxidants or caspase inhibitors and by intracellular expression of Bcl-2, Beclin-1, or protease inhibitors. Older animals survive infection unless infected with a neurovirulent strain of SINV. In these mice, anterior horn motor neurons die by a primarily necrotic process that is influenced by excitotoxic amino acids and inflammation, whereas hippocampal neurons can be either apoptotic or necrotic. Death also occurs in uninfected neurons in the vicinity of infected neurons and can be delayed or prevented by treatment with glutamate receptor antagonists.
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PMID:Neuronal cell death in alphavirus encephalomyelitis. 1579 51


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