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The biochemistry of neuronal necrosis: rogue biology?

Key Points

  • Necrosis is a form of inappropriate cell death that contributes to several pathological conditions in humans. Despite the significant impact of necrosis on human health, its molecular mechanisms have remained poorly understood. This is partly due to the lack of tractable genetic models and the pervasive idea that necrosis is simply the chaotic obliteration of cells.

  • Recent studies have revealed common general trends in necrotic cell death that point towards a limited repertoire of biochemical cascades that enact cell destruction. These mechanisms — unlike most apoptotic pathways — did not evolve to specifically effect necrosis. Instead, they represent normal physiological processes that become destructive under adverse conditions.

  • Mechanisms of ion homeostasis are principal determinants of necrosis. Several diverse necrosis-initiating insults converge to perturb ionic balance beyond a crucial threshold, thereby triggering cell demise. Increase of intracellular calcium concentration and acidification can both induce and aggravate necrotic cell death.

  • Similarly to apoptosis, protein degradation mechanisms are involved in the execution of necrosis. Calpain and cathepsin proteases are key in the dismantling of the cell during necrotic cell death. In addition, caspases — the central executioners of apoptosis — and the proteasome have also been implicated in necrosis.

  • Intervention strategies that aim to counter necrosis have met with encouraging success. Several experimental models of necrotic cell death have been established in simple organisms that are amenable to genetic analysis, such as Caenorhabditis elegans and Drosophila melanogaster. These models should help in the dissection of the biochemistry of necrosis, providing knowledge that is essential for the development of effective protective measures against necrosis.

Abstract

When stressed beyond their tolerance, cells undergo necrosis, an acute, non-apoptotic form of cell death. Necrosis is crucial to the damage that injury and disease inflict on the nervous system. Recent discoveries have shed light onto the molecular requirements for necrosis, and provide new evidence that, as is the case for apoptosis, the mechanisms of necrotic cell death are conserved from nematodes to humans. But in contrast to apoptotic mechanisms, necrotic mechanisms did not evolve specifically to carry out necrosis. Instead, under extreme circumstances, normal cellular activities are destabilized with devastating consequences for the cell. Here, we review the mechanisms that are implicated in necrosis and discuss the events that transform them to catastrophic for cell survival.

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Figure 1: Necrotic cell death.
Figure 2: Neurodegenerative disease in Caenorhabditis elegans.
Figure 3: Calcium homeostasis mechanisms.
Figure 4: Proteases effecting necrosis.
Figure 5: Deadly proteolytic cascades in the nematode.

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Acknowledgements

We gratefully acknowledge the contributions of numerous investigators whose work we did not include in this review owing to space limitations. We thank our colleagues at IMBB for discussions and comments on the manuscript. Work at the authors' laboratory is supported by EMBO and the IMBB intramural fund. N.T. is an EMBO Young Investigator.

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Correspondence to Nektarios Tavernarakis.

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DATABASES

OMIM

Amyotrophic lateral sclerosis

Alzheimer disease

Huntington disease

Parkinson disease

WormBase

acy-1/sgs-1

age-1

ASP-3

ASP-4

CLP-1

daf-2

DEG-1

deg-3

des-2

gsa-1

MEC-4

mec-6

TRA-3

FURTHER INFORMATION

The Tavernarakis Lab

Glossary

ISCHAEMIA

The insufficient supply/flow of blood, usually due to a blocked vessel. Ischaemia in the brain can lead to a stroke. About 80% of all strokes are ischaemic. Most blockages in the cerebral blood vessels are due to a blood clot, often in an artery narrowed by plaque.

KARYOLYSIS

Disintegration of the nucleus.

PARAPTOSIS

An alternative form of cell death that does not seem to involve caspases. In addition, paraptosis induces changes in cellular morphology that are distinct from those generated by apoptosis and bear similarity with features of necrosis. For example, there is no prominent chromatin condensation, whereas there is extensive cytoplasmic vacuolation. Unlike necrosis, however, paraptosis requires de novo protein synthesis, similarly to apoptosis.

DEGENERINS

A group of proteins first described in Caenorhabditis elegans, which can mutate to cause neurodegeneration. Degenerins are ion channels with roles in sensory transduction and ionic homeostasis. Nematode proteins share sequence similarity with vertebrate epithelial sodium channels (ENaCs) and some Drosophila proteins such as Ripped Pocket (RPK) and Pickpocket (PPK).

NEURONAL CEROID LIPOFUSCINOSIS

Condition caused by lack of the enzyme palmitoyl-protein thioesterase, which is involved in the catabolism of lipid-modified proteins. The absence of this protein is thought to be responsible for the disease by allowing a waste product (ceroid lipofuscin) to accumulate in neurons.

MND MOUSE

Motor neuron degeneration mouse. A naturally occurring mutant mouse that shows abnormalities similar to those of the human neuronal ceroid lipofuscinosis.

WOBBLER MOUSE

The wobbler mutation causes muscle weakness due to motor neuron degeneration and a defect in spermatogenesis. The wobbler mouse is used as an animal model for human spinal muscular atrophies.

PARAOXONASE

A serum protein that is bound to high-density lipoproteins (HDLs), made in the liver and delivered to the bloodstream. The physiological function of paroxonase is unknown, but a role in lipid metabolism has been postulated.

SERCA

Sarco-endoplasmic reticulum calcium ATPase. A pump that sequesters calcium to the endoplasmic reticulum at the expense of ATP. SERCA, which comprises one of the main mechanisms for maintaining calcium homeostasis in the cytoplasm, is inhibited by the drug thapsigargin, which is extracted from the seeds of the plant Thapsia garganica.

MITOCHONDRIAL PERMEABILITY TRANSITION

(MPT). A non-specific increase in the permeability of the inner mitochondrial membrane that occurs when matrix calcium is greatly increased, especially under oxidative stress and adenine nucleotide depletion. MPT is associated with the opening of a non-specific pore in the mitochondrial inner membrane, which transports molecules that are smaller than 1,500 Daltons.

HYPERCAPNEA

A state of increased partial pressure of CO2 in the blood. Hypercapnea is usually accompanied by a decrease of oxygen in the bloodstream.

AUTOPHAGY

A catabolic process by which cells degrade and digest their own cytoplasmic constituents, usually through the action of lysosomal enzymes. One of the most distinguishing features of autophagy is the dynamic rearrangement of cellular membrane to sequester cytosol and organelles into autophagosomes for delivery to the lysosome or vacuole. Autophagy is crucial for cell maintenance and development, and has also been linked to a growing number of human diseases, including neurodegenerative conditions, cardiovascular disease and breast cancer.

TAU

A neuronal protein that binds to microtubules, promoting their assembly and stability.

NEUROFIBRILLARY TANGLES

Large filamentous tau aggregates within neurons, usually prominent in the cerebral cortex, and hippocampus. Neurofibrillary tangles are common in the brains of patients with Alzheimer's disease.

NIEMANN–PICK DISEASE

A recessive metabolic disorder of lysosomal storage that results in a build-up of sphingomyelin and cholesterol.

FODRIN

A non-erythroid cell, spectrin like protein. Fodrin forms a two-dimensional mesh beneath the plasma membrane and seems to be involved in stabilizing membrane structures, maintaining cell shape and linking the cytoskeleton to plasma membrane or intracellular vesicles. In particular, fodrin mediates the association of actin filaments with the plasma membrane and is a well-known substrate for calpain.

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Syntichaki, P., Tavernarakis, N. The biochemistry of neuronal necrosis: rogue biology?. Nat Rev Neurosci 4, 672–684 (2003). https://doi.org/10.1038/nrn1174

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