Abstract
Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
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Acknowledgements
This work was supported by grants from the US National Institute of Neurological Disorders and Stroke (1R01NS082257) and the US National Institute on Aging (1R01AG047231, R21AG059073 and RF1AG055521) (to J.Y.).
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Nature Reviews Neuroscience thanks S. Finkbeiner, D. Rubinsztein and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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J.Y. is a consultant for Denali Therapeutics. P.A. declares no competing interests. D.O. is an employee of Sanofi.
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Glossary
- Death receptors
-
(DRs). The receptors for tumour necrosis factor (TNF), FAS ligand (FASL) and TNF-related apoptosis-inducing ligands (TRAILs) that contain an intracellular protein–protein interaction domain known as the death domain and that can mediate cell death.
- Extrinsic cell death
-
Cell death pathways such as extrinsic apoptosis and necroptosis that are activated upon stimulation of tumour necrosis factor (TNF) receptor 1 (TNFR1), FAS and certain TNF-related apoptosis-inducing ligand (TRAIL) receptors by their cognate ligands.
- Intrinsic apoptosis
-
An apoptosis pathway that can be activated upon mitochondrial damage and that activates downstream caspases such as caspase 3.
- Middle cerebral artery occlusion
-
(MCAo). A mouse model of stroke induced by the insertion of a filament into the carotid artery to block cerebral blood flow and induce tissue damage in the brain.
- Experimental autoimmune encephalomyelitis
-
(EAE). An animal model of multiple sclerosis induced by immunizing with purified myelin, peptides from myelin-derived proteins or passive transfer of T cells reactive to these myelin proteins.
- Immune silent
-
A state that does not induce immune activation or an inflammatory response.
- Death domain
-
(DD). A protein–protein interaction module composed of a bundle of six α-helices.
- RIPK1-dependent apoptosis
-
(RDA). RIPK1-dependent activation of caspase 8 and consequent apoptosis, initially triggered by tumour necrosis factor in cells deficient in transforming growth factor-β-activated kinase 1 (TAK1), TBK1 or inhibitor of apoptosis 1 (IAP1) and IAP2. RDA can be inhibited by receptor-interacting protein kinase 1 (RIPK1) inhibitors.
- DFG-out conformation
-
The inactive conformation of the T-loop motif of a kinase, such as RIPK1.
- Type II kinase inhibitor
-
A kinase inhibitor that inactivates the kinase by binding a hydrophobic pocket adjacent to the ATP-binding site. Type II kinase inhibitors are more specific than type I kinase inhibitors, which bind to the ATP-binding pocket itself.
- DNA-encoded libraries
-
Synthetic chemical libraries made by conjugating chemical compounds or building blocks to short DNA fragments that serve as identification bar codes.
- Wallerian degeneration
-
The degeneration of a distal axon after a nerve fibre is injured. It is independent of neuronal cell body loss but may contribute to eventual neuronal loss.
- Cuprizone model
-
A rodent model of oligodendrocyte death and reversible demyelination that is induced by feeding with the copper chelator cuprizone.
- Decompaction
-
Immature axon myelination pattern with loosely packed myelin sheath.
- PC12 cells
-
A cell line derived from a pheochromocytoma of the rat adrenal medulla.
- Lysosomal storage disease
-
A diseases that results from defects in lysosomal function owing to mutations in genes involved lipid metabolism and that often leads to neurodegeneration (for example, Gaucher disease).
- Braak stage
-
A pathology scoring system used for both Alzheimer disease and Parkinson disease that refers to the extent of the distribution of neuropathology in these diseases.
- Autophagy
-
A cellular mechanism involving the formation of double-membrane vesicles, known as autophagosomes, that fuse with lysosomes, in which the contents are degraded and recycled.
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Yuan, J., Amin, P. & Ofengeim, D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 20, 19–33 (2019). https://doi.org/10.1038/s41583-018-0093-1
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DOI: https://doi.org/10.1038/s41583-018-0093-1
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