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  • Review Article
  • Published:

Adult neuron survival strategies — slamming on the brakes

Key Points

  • Programmed cell death (PCD) is crucial for nervous system development, but in the mature nervous system the imperative shifts — neurons need to survive for the lifetime of the organism, and to live becomes the default. To prevent inadvertent activation of apoptosis in these neurons, anti-apoptotic survival factors are induced that function as powerful 'brakes' to prevent activation of the execution phase of apoptosis.

  • In developing neurons, the 'decision' to die depends both on the subcellular location of members of the BCL2 (B-cell leukaemia/lymphoma-2) family, and the presence/activity of anti-apoptotic brakes. The BCL2 family consists of three main subgroups, which are categorized according to their anti- or pro-death function and the presence or absence of conserved structural motifs — the BCL2 homology (BH) domains.

  • Although trophic factor absence or withdrawal is responsible for PCD during development, this is not a primary mechanism of apoptosis in mature neurons — instead, the positive presence of diverse apoptosis-inducing signals is responsible for causing apoptosis. Two principal pathways lead to apoptosis in mature neurons — the 'extrinsic' or death receptor-initiated pathway, and the 'intrinsic' or mitochondrial pathway.

  • Adult neuronal death can also occur by necrosis, an unregulated cell death that is the direct result of external insults such as physical injury, energy depletion, toxic insults, hypoxia and ischaemia. Necrosis typically evokes an inflammatory response and leads to cell swelling, disruption of nuclear and cytoplasmic integrity, and widespread death of regional groups of cells.

  • An anti-apoptotic brake is an intrinsic molecule that can inhibit the apoptotic pathway at one or more points to promote neuronal survival. A cohort of molecules with anti-apoptotic properties or the ability to promote cell survival pathways are induced following acute or chronic neuronal injury, including anti-apoptotic members of the BCL2 family, heat shock proteins, inhibitor of apoptosis proteins, uncoupling proteins and activated protein C.

  • Apoptotic brakes can be categorized on the basis of their primary site of anti-apoptotic action, as molecules that take effect upstream of mitochondria, at the mitochondrion to prevent the release of cytochrome c and other pro-apoptotic factors, or downstream of mitochondria on effector molecules such as the apoptosome and caspases.

  • Apoptosis can be suppressed upstream of mitochondria by two main strategies — decoy receptor or ligand proteins, and sequestration or inhibition of pro-apoptotic proteins. Apoptotic brakes that function at the level of the mitochondrion prevent mitochondrial membrane permeabilization and release of apoptotic factors into the cytosol. Downstream of the mitochondria, intrinsic brakes can suppress activation of the executioners of apoptosis, caspases 3, 7 and 9.

  • An important challenge will be to identify all the anti-apoptotic brakes that are expressed in neurons, along with their mechanisms of action and regulation, and to determine whether induction of specific combinations of anti-apoptotic molecules in selected neuronal populations is beneficial for the treatment of neurological and neurodegenerative diseases.

Abstract

Developing neurons are programmed to die by an apoptotic pathway unless they are rescued by extrinsic growth factors that generate an anti-apoptotic response. By contrast, adult neurons need to survive for the lifetime of the organism, and their premature death can cause irreversible functional deficits. The default apoptotic pathway is shut down when development is complete, and consequently growth factors are no longer required to prevent death. To protect against accidental apoptotic cell death, anti-apoptotic mechanisms are activated in mature neurons in response to stress. Loss or reduced activity of these intrinsic anti-apoptotic 'brakes' might contribute to or accelerate neurodegeneration, whereas their activation might rescue neurons from injury or genetic abnormalities.

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Figure 1: Overview of apoptotic mechanisms in neurons.
Figure 2: Extrinsic and intrinsic apoptotic signalling pathways in neurons.
Figure 3: Neuronal anti-apoptotic brakes upstream of mitochondria.
Figure 4: Anti-apoptotic brakes at the mitochondrion.
Figure 5: Anti-apoptotic brakes downstream of the mitochondria.

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Acknowledgements

We thank the NIH and the Muscular Dystrophy Association for financial support.

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Authors and Affiliations

Authors

Corresponding author

Correspondence to Clifford J. Woolf.

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The authors declare no competing financial interests.

Supplementary information

Related links

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DATABASES

Entrez Gene

AIF

BAR

BAX

BCL2

BID

DAXX

FAS

FASL

HSP27

HTRA2

NRAGE

SMAC/DIABLO

SODD

TNFR1

UCP

XIAP

OMIM

Alzheimer's disease

Huntington's disease

Parkinson's disease

FURTHER INFORMATION

Biocarta

Apoptosis pathway

Mitochondrial apoptosis

Survival pathway

Brown's laboratory

Woolf's laboratory

Glossary

DORSAL ROOT GANGLIA

The cell bodies of primary sensory neurons are found in paired ganglia that lie alongside the spinal cord. These cell bodies are surrounded by satellite glial cells, which share much in common with the Schwann cells that ensheath peripheral axons.

SYMPATHETIC NEURONS

The neurons of the sympathetic nervous system, which is responsible for such physiological effects as reduction of digestive secretions, vasoconstriction and increased heart rate, thereby opposing the effects of the parasympathetic nervous system.

AMYOTROPHIC LATERAL SCLEROSIS

A progressive neurological disease that is associated with the degeneration of upper and lower spinal motor neurons. This neuron loss causes muscles to weaken and waste away, leading to paralysis.

MICROGLIA

Phagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

EXCITOTOXIN

A chemical toxin — typically a structural analogue of the neurotransmitter glutamate — that, when injected into brain tissue, kills cell bodies in the region of injection, leaving fibres of passage through that region intact. The neurotoxic effect of these agents is mediated by their action at glutamate receptors and involves overstimulation of the neuron, leading to cell death.

OXIDATIVE STRESS

A disturbance in the pro-oxidant–antioxidant balance in favour of the former, leading to potential cellular damage. Indicators of oxidative stress include damaged DNA bases and protein oxidation and lipid peroxidation products.

UNFOLDED PROTEIN RESPONSE

An intracellular signalling pathway that connects the endoplasmic reticulum (ER) with the nucleus. Under stress conditions (when unfolded proteins accumulate in the ER), cells react by the increased transcription of chaperone genes. These chaperones are required for maintenance of protein folding.

CHAPERONES

Proteins that mediate the folding or assembly of another polypeptide, but do not form part of the completed structure or participate in its biological function.

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Benn, S., Woolf, C. Adult neuron survival strategies — slamming on the brakes. Nat Rev Neurosci 5, 686–700 (2004). https://doi.org/10.1038/nrn1477

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