Table 1. Summary of cell death mechanisms discussed in this review.
| Type of neuronal cell death | Initiators | Mediators | Executioners | Inhibitors | Outcome | References |
|---|---|---|---|---|---|---|
| Apoptosis | Death receptors, DNA damage, ROS, staurosporine | Intrinsic: pro-apoptotic Bcl2 members (Bax, Bim, Bak, Puma, Noxa), Bcl2 inhibitors (ABT737), extrinsic: upstream caspases 8/10 | Apoptosome (cytochrome c/apaf1 activation (dATP- > dADP exchange) to caspase 9 and downstream caspases mitochondrial Smac/diablo inhibits IAP/xIAPs | Natural: anti-apoptotic Bcl2 members (Bcl2, BclxL, McL1) IAP/XIAP family of caspase inhibitors, caspase activity inhibitors (only temporary) | DNA breaks, nuclear condensation, loss of MOMP, exposure of PtdSer, removal by phagocytosis Eventual ATP depletion and secondary necrosis | [4,5,81] |
| Ferroptosis (oxytosis) | Fe3+ entry via transferrin receptor and conversion into Fe2+ lack of cysteine supply via Xc− transporter | Oxygen/hydroxyl radicals (via the Fenton reaction), and/or chemical GPx4 inhibitors (1S, 3E-RSL3) | Loss of glutathione, Lipid reactive oxygen species (LOOH, L–O], preferential oxidation of polyunsaturated fatty acids (PUFAs) | Glutathione peroxidase 4 (GPx4; up-regulation by Nrf2), antioxidants (ferrostatin-1, liproxstatin-1, vitamin E) iron chelators (Deferoxamine) | Plasma membrane lipid fragmentation, mitochondrial shrinkage/deformation of cristae, loss of ATP and NAD+, lysosomal membrane permeabilisation | [82–85] |
| Pyroptosis | Pattern recognition receptors (PRRs)/other signals (bacteria/toxins/dsDNA breaks) | Inflammasome (NLRP3 or its homologues/apoptosis-associated speck-like protein containing CARD (ASC/procaspase‐1) but also other mechanisms | Gasdermins (GSDMs), especially GSDMD, activated by caspase-1 cleavage downstream of inflammasome formation | Disulfiram (via Cys191/192 human/mouse in GSDMD) | Large pores with electrostatic filtering (preference for positively charged/neutral molecules) but no notable cell swelling can mediate IL-1b export | [86–90] |
| Necroptosis | Death receptors (TNF), caspase-8 inhibition | RIPK1/TRIF/ZBP1 binding to RIPK3 and phosphorylation of MLKL | Phospho-MLKL oligomerisation and translocation to plasma membrane | Necrostatins (RIPK1 inhibitors) | Pores in plasma membrane (and mitochondria/lysosomes); Na+ permeability, water influx, and osmotic swelling morphology | [36,37,91–93] |
| Parthanatos | Poly(ADP-ribose) polymerase 1 (PARP-1) hyperactivation | Apoptosis inducing factor (AIF)-dependent and microphage migration inhibitory factor (MIF)-dependent | DNA degradation | PARP inhibitors | Shrunken and condensed nuclei, membranes disintegrate, and cells become propidium iodide-positive within a few hours after the onset | [94,95] |
| Autosis* | Hyper autophagy activation | Ions | Osmotic imbalance | Autosis - NaKATpase inhibitors, e.g. ouabain or autophagy inhibitors | Nuclear shrinkage; focal separation of inner and outer nuclear membranes with focal expansion of perinuclear space Extensive cytoplasmic vacuolisation increased adhesion | [96,97] |
| Primary phagocytosis† | Inflammation, stress LPS activation of microglia; ROS induced by tau aggregates | Phosphatidylserine/calreticulin exposure on the target cell | Opsonins (MFGE8, Gas6, protein S) made by phagocyte | CD47, excess AnnexinV or synaptotagmin C2 domain | Phagocytosis of live cell, inhibition of phagocytosis leaves behind a live cell | [50,57,98,99] |
| Perforin/Granzyme B | Cytotoxic T cells (CTLs) and natural killer (NK) cells | Ionic pores | Granzyme proteolysis and other activities | unknown | Stored as granules. Perforin creates ionic pores in the target cell, granzymes facilitate cell death by various mechanisms | [6,100,101] |
*
Forms of lysosome-dependent cell death, and autophagy-dependent cell death are not included because their molecular mechanisms are not proven except in invertebrates.
†
Also named ‘phagoptosis’ although there is no ‘ptosis’ element in this form of death.