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Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology

Key Points

  • Caspases are an integral mediator of programmed cell death during development in the CNS, although experiments using mice deficient in various caspases suggest that there is substantial complexity and redundancy in the apoptotic cascades that ultimately lead to the efficient removal of unnecessary and extra neurons.

  • Caspase activation can occur as a consequence of either intrinsic or extrinsic signals, and can be expressed in a variety of ways including classical apoptosis or necroptosis in the mature nervous system, which are involved in cell death after acute injury and in slowly progressive neurodegenerative diseases.

  • Caspases may have a special role in the CNS, such as sculpting the axonal and dendritic processes that refine the nervous system both during development and in the adult brain.

  • Recent data suggest that localized, restricted activation of caspases, even so-called executioner caspases, is an integral part of normal signalling in mature neuronal circuits and synaptic biology.

  • Local, non-apoptotic activation of caspases may also occur in neurodegenerative processes, whereby caspase activation leads to cleavage of substrates such as tau, which may then contribute to the formation of classical neuropathological lesions such as neurofibrillary tangles.

Abstract

Caspases are cysteine proteases that mediate apoptosis, which is a form of regulated cell death that effectively and efficiently removes extra and unnecessary cells during development. In the mature nervous system, caspases are not only involved in mediating cell death but also regulatory events that are important for neural functions, such as axon pruning and synapse elimination, which are necessary to refine mature neuronal circuits. Furthermore, caspases can be reactivated to cause cell death as well as non-lethal changes in neurons during numerous pathological processes. Thus, although a global activation of caspases leads to apoptosis, restricted and localized activation may control normal physiology and pathophysiology in living neurons. This Review explores the multiple roles of caspase activity in neurons.

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Figure 1: Caspase activation occurs in response to various stimuli.
Figure 2: Role of caspase activation in normal synaptic physiology.
Figure 3: Caspase-cleaved tau is a component of neurofibrillary tangles.

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Correspondence to Bradley T. Hyman or Junying Yuan.

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Glossary

Apoptosis

A form of regulated cell death that is controlled by the members of the caspase family and BCL-2 family of proteins.

Programmed cell death

Cell death that is regulated by genetically encoded mechanisms.

BCL-2 homology domains

Protein–protein interacting domains found in the members of the BCL-2 family of proteins. The members of the BCL-2 family share one or more of the four BH domains (BH1, BH2, BH3 and BH4) that mediate the interactions among different members of the BCL-2 family.

Caspase recruitment domain

(CARD). A protein–protein interacting motif frequently found in proteins associated with apoptosis and inflammation.

Death effector domain

(DED). A protein–protein interacting motif found in proteins that mediate caspase activation and apoptosis.

Death-inducing signalling complex

(DISC). Intracellular signalling complexes associated with the receptors in the tumour necrosis receptor 1 superfamily that are involved in mediating cell death.

Exencephaly

A type of developmental abnormality whereby the brain may protrude outside the skull.

Necroptosis

A necrotic cell death mechanism regulated by the RIP1 and RIP3 kinases.

Long-term depression

(LTD). An electrophysiological paradigm that changes synaptic strength following specific electrical or chemical stimuli. It is widely thought to be a model of neuronal plasticity of relevance in learning and memory.

TUNEL

Terminal deoxynucleotidyl transferase dUTP nick end labelling. A method for detecting DNA fragmentation by labelling the terminal end of nucleic acids found in apoptotic cells.

z-VAD.fmk

Carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone. A cell-permeable, peptide-based pan-caspase inhibitor that irreversibly binds to the catalytic site of caspases and leads to inhibition of apoptosis.

z-DEVD.fmk

Benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone. A cell-permeable, irreversible peptide-based inhibitor of caspase 3.

TDP43

A small RNA-associated protein in which mutations and intracellular inclusions are associated with neurodegenerative phenotypes. Hyperphosphorylated and ubiquitinylated neuronal inclusions are found in ubiquitin-positive, tau-negative forms of frontotemporal dementia and in some cases of amyotrophic lateral sclerosis.

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Hyman, B., Yuan, J. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat Rev Neurosci 13, 395–406 (2012). https://doi.org/10.1038/nrn3228

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