Neuronal cell death is associated with most of the major diseases that afflict the CNS. Stem cell therapeutics holds promise for replacing degenerating or ablated . Programmed cell death (PCD) has a critical role in the development of the .. BAR, which is expressed primarily in neurons of the central nervous system, also . Even though this finding highlights a physiological role for programmed cell death in the CNS, the functional consequences remain rather underwhelming in the.
Death CNS Cell
In ALS, evidence is building that actions on or originating in the mitochondria may be an important part of the disease. Interestingly, changes in the mitochondria can be detected before one can find a physical change, such as hind limb weakness in mice. In addition, mitochondria show damage early in the ALS disease process, a finding that is leading researchers to study this cell component intensively. Important clues on the roles involving mitochondria undoubtedly will surface as scientists probe further into the details.
Nerve cells pass signals to each other and to their target organs by releasing messenger molecules, called neurotransmitters. Many are simple amino acids such as the one called glutamate. The message is intended to tell the recipient neuron whether to fire off its own neurotransmitters. As with all neurotransmitters, glutamate docks at specific recognition molecules on the receiving neuron.
Glutamate is then swiftly cleared from the nerve cell junctions to keep the message brief. Prolonged excitation of the nerve cell can occur from too much glutamate, which is toxic. Neurobiologists recognize that glutamate can cause harm when the messages are overwhelming, as in stroke or epilepsy. Molecules called transporters aid in keeping glutamate in proper concentrations around nerve cells. Abundant evidence points to glutamate as a destructive factor in ALS and investigators are working to find out how this can be changed.
Gene therapy approaches are under investigation to deliver glutamate transporters to cells affected by ALS. Other avenues towards control of glutamate in ALS are also under active investigation.
The first approved specific treatment for ALS is riluzole, a drug that modulates glutamate. It is a process that should help heal. But sometimes the inflammation that accompanies illness or injury is counterproductive. Inflammation in the central nervous system is called neuroinflammation. There is increasing evidence that neuroinflammation accompanies the death of motor neurons in ALS.
However, evidence so far does not support that ALS is an autoimmune disease. The inflammatory process apparently is a reaction to the death of the cells, and not the instigator. Footnotes Abbreviations used in this paper: Manganese-enhanced MRI reveals structural and functional changes in the cortex of Bassoon mutant mice.
Glycinergic and GABAergic synaptic activity differentially regulate motoneuron survival and skeletal muscle innervation. Trophic factors and neuronal survival. Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR.
Receptors that mediate cellular dependence. Neuromuscular development in the absence of programmed cell death: Adaptive roles of programmed cell death during nervous system development. Local control of neurite development by nerve growth factor. Apoptosis regulates ipRGC spacing necessary for rods and cones to drive circadian photoentrainment.
Genetic control of programmed cell death during animal development. Architects in neural circuit design: Glia control neuron numbers and connectivity.
Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning. FasL, Fas, and death-inducing signaling complex DISC proteins are recruited to membrane rafts after spinal cord injury. Placement of the BCL2 family member BAX in the death pathway of sympathetic neurons activated by trophic factor deprivation.
Programmed cell death in neuronal development. Directed expression of NGF to pancreatic beta cells in transgenic mice leads to selective hyperinnervation of the islets. Genetic control of programmed cell death in the nematode C. Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons.
Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity. Severe sensory and sympathetic deficits in mice lacking neurotrophin Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases.
Redox regulation of the intrinsic pathway in neuronal apoptosis. The dependence receptor DCC requires lipid raft localization for cell death signaling. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. The role of cell death during neocortical neurogenesis and synaptogenesis: Endocytosis of activated TrkA: History of the discovery of neuronal death in embryos.
Neuronal death in the spinal ganglia of the chick embryo and its reduction by nerve growth factor. Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain.
Activity-dependent regulation of neuronal apoptosis in neonatal mouse cerebral cortex. Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels. Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning. NGF signaling from clathrin-coated vesicles: Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology.
Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Loss of survivin in neural precursor cells results in impaired long-term potentiation in the dentate gyrus and CA1-region. Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development.
Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Natural variation and genetic covariance in adult hippocampal neurogenesis. Impaired migration in the rostral migratory stream but spared olfactory function after the elimination of programmed cell death in Bax knock-out mice.
The maintenance of specific aspects of neuronal function and behavior is dependent on programmed cell death of adult-generated neurons in the dentate gyrus. The trk proto-oncogene encodes a receptor for nerve growth factor. Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: Caspases 3 and 7: Strain-dependent neurodevelopmental abnormalities in caspasedeficient mice.
Suppression of the intrinsic apoptosis pathway by synaptic activity. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization.
Axon retraction and degeneration in development and disease. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Expression of the trk proto-oncogene is restricted to the sensory cranial and spinal ganglia of neural crest origin in mouse development. Relationship of the time of origin and death of neurons in rat somatosensory cortex: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
Distinct modes of neuron addition in adult mouse neurogenesis. Inhibitor of apoptosis proteins in eukaryotic evolution and development: Cell death of motoneurons in the chick embryo spinal cord. The loss of motoneurons following removal of afferent inputs. Cell death during development of the nervous system. Brain-derived neurotrophic factor rescues developing avian motoneurons from cell death.
The rescue of developing avian motoneurons from programmed cell death by a selective inhibitor of the fetal muscle-specific nicotinic acetylcholine receptor. Maturation and death of adult-born olfactory bulb granule neurons: Neuromuscular blockade increases motoneurone survival during normal cell death in the chick embryo.
Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells. A molecular basis for trophic interactions in vertebrates.
Neuronal death during development. Principles of Neural Development. ER stress triggers apoptosis by activating BH3-only protein Bim. Axonal self-destruction and neurodegeneration. Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth.
TrkA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry. Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. This idea is compatible with the findings that therapeutics aimed at different pathways for example, caspase activation, mitochondrial release of cytochrome c , metal binding and reactive-oxygen-species scavenging all have partly salutary effects. However, it also suggests that a complete halt of the neurodegenerative process may require therapeutics that address all the interacting pathways of the network.
Neuronal loss is a relatively late event in neurodegenerative diseases, following neuronal dysfunction, synapse loss and, often, somal atrophy. But targeting PCD has been successful in at least some model systems of neurodegeneration, and it is possible that targeting multiple PCD pathways will be even more effective.
Caspase inhibition in vivo retarded the degeneration in transgenic mouse models of both ALS and HD, despite the fact that the morphological description of neuronal cell death in these diseases is not compatible with apoptosis 49 , Bcl-2 expression in a transgenic model of ALS delayed symptom onset and increased lifespan, but did not alter the disease duration Minocycline, a second-generation tetracycline that inhibits mitochondrial cytochrome c release, effected neuroprotection in mouse models of HD, PD and ALS Minocycline is orally bioavailable, penetrates the blood—brain barrier and has been proved safe for use in humans.
Rasagiline, which has been approved for the treatment of PD, has also been proposed to target apoptosis, but because it is a potent, selective, irreversible inhibitor of monoamine oxidase type B, its therapeutic effect on PD may have nothing to do with effects on apoptosis. Trophic factors have multiple effects, including the inhibition of apoptosis, the stimulation of neural precursors and the stimulation of neurite outgrowth. The literature is rife with examples of trophic-factor therapy for various neurological conditions, and although many have been unsuccessful, the delivery of the correct factor s to the right target in the correct concentration for a particular disease still holds great promise although hyperactivation of at least some trophic-factor receptors may induce PCD.
A recent study of fibroblast growth factor 2 FGF2 in a mouse model of HD prolonged survival, improved motor performance and reduced polyglutamine aggregates A number of approaches have been taken to deliver nerve growth factor NGF to patients with AD, the most recent being by means of genetically engineered fibroblasts in a phase I trial In this study, improvements in cognition and positron-emission tomography used to monitor fluorodeoxyglucose uptake were documented.
HD may represent one of the best possibilities for trophic-factor therapy: Furthermore, cysteamine has been shown to increase BDNF levels in brain Exciting recent evidence suggests that pathological processes may stimulate neurogenesis in the brain and may redirect the migration of nascent neurons towards the site of pathology.
And, under certain circumstances, stimulating neurogenesis can improve the performance and survival of mice with neurodegenerative disease. These and similar results raise the question of whether stem-cell exhaustion or senescence after prolonged stimulation might have a role in the long-term course of neurodegenerative disease.
Furthermore, although the factors linking neurodegeneration to neural-stem-cell proliferation and inhibition of PCD are largely unknown, the potential for therapy using these putative factors is likely to be significant. Reconciliation of cell-death pathways with neurodegenerative and regenerative mechanisms should offer an improved understanding of disease and open avenues for therapeutic intervention. We apologize to all colleagues whose papers we were unable to cite owing to space limitations.
Chen for critical reading of the manuscript, and M. Abulencia for manuscript preparation. The authors declare no competing financial interests. National Center for Biotechnology Information , U. Author manuscript; available in PMC Mar Bredesen , 1, 2 Rammohan V. Rao , 1 and Patrick Mehlen 1, 3. Author information Copyright and License information Disclaimer. Correspondence should be addressed to D. The publisher's final edited version of this article is available at Nature.
See other articles in PMC that cite the published article. Table 1 Characteristics of dying cells. Open in a separate window. Box 1 Intrinsic and extrinsic apoptotic pathways. Origami meets apoptosis Misfolded proteins are constantly being produced, and for some proteins such misfolded species represent a significant fraction of the overall output. Box 2 Endoplasmic-reticulum stress and cell death. Autophagic cell death Desperate times call for desperate measures, and cells have a host of protective stress responses, most of which switch into execution mode during prolonged activation.
Alternative cell-death programmes In comparison with apoptosis, little is known about autophagic PCD, and even less is known about other non-apoptotic forms of PCD. Triggering cell death in neurodegeneration As noted above, a number of different and potentially interrelated insults may occur as part of the neurodegenerative process.
Targeting programmed cell death Neuronal loss is a relatively late event in neurodegenerative diseases, following neuronal dysfunction, synapse loss and, often, somal atrophy. A lifeline Exciting recent evidence suggests that pathological processes may stimulate neurogenesis in the brain and may redirect the migration of nascent neurons towards the site of pathology.
Acknowledgements We apologize to all colleagues whose papers we were unable to cite owing to space limitations. Footnotes The authors declare no competing financial interests. Lehrbuch der vergleichende mikroskopischen Anatomie der Wirbeltiere.
The nerve growth factor: Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. Naturally occurring neuron death and its regulation by developing neural pathways. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. The morphology of various types of cell death in prenatal tissues. An alternative, non-apoptotic form of programmed cell death. Naturally occurring cell death during neural development. Fadok VA, et al.
Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.
Thornberry NA, Lazebnik Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase Rao RV, et al.
Coupling endoplasmic reticulum stress to the cell death program. An Apafindependent intrinsic pathway. Yuan J, Yankner BA. Caspase activity sows the seeds of neuronal death. Green DR, Kroemer G. Pharmacological manipulation of cell death: The protein structures that shape caspase activity, specificity, activation and inhibition. Kopito RR, Ron D. Toxic proteins in neurodegenerative disease. Sitia R, Braakman I.
Quality control in the endoplasmic reticulum protein factory. Cellular defenses against unfolded proteins: Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Scorrano L, et al. Chae HJ, et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Endoplasmic reticulum stress-induced apoptosis: Hegde RS, et al. A transmembrane form of the prion protein in neurodegenerative disease.
Levine B, Yuan J. Autophagy in cell death: Komatsu M, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.
Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Shimizu S, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Yu L, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase Autophagic programmed cell death by selective catalase degradation.
Gomez-Santos C, et al. The biochemistry of apoptosis. Sperandio S, et al.
CNS cell death a result of tamoxifen exposure
(6) that programmed cell death in a major population of neurons in the central nervous system (CNS) is caused by an intrinsic program independent of external . Feb 23, C. elegans, cells undergo programmed cell death, with. of them fects in various organs, including the CNS (Buss et al., ;. Miura. The terminal step in the apoptotic program is the removal of dying cells by phagocytes. Apoptotic cell clearance, an evolutionarily conserved process.