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Necroptosis, a Potential Therapeutic Target for Neurological Disorders

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  • First Online:
Handbook of Neurotoxicity

Abstract

Necrosis is considered to be an unregulated and chaotic cell death. However, recent advances in cell death strategies support necroptosis as a form of regulated programmed necrotic cell death. In response to TNF-α or Fas ligands, necroptosis can be induced by cell death receptors in multiple cell lines in the presence of a caspase inhibitor z-VAD; necroptotic cell death has been found to play an important role in normal development, immunity, inflammation, cancer, and human diseases. In this chapter, the molecular mechanisms governing necroptosis, recent findings about the upstream and downstream schema of necroptosis, and potential therapeutic targets in neurological disorders are discussed. After being activated by TNF-α (or Fas ligands) and death receptors, receptor-interacting proteins 1 and 3 (RIP1 and RIP3) form a complex, which play a central role in the induction of necroptosis. RIP3 phosphorylates and activates mitochondrial proteins mixed lineage kinase domain-like protein (MLKL) and PGAM5, resulting in the execution of necroptosis by dynamin-related protein 1, the GTPase that controls mitochondrial fission. Some small molecules such as necrostain-1 and necrosulfonamide target different steps of necroptosis and impede the progress of necroptosis. FADD, caspase-8, CLIP, and CYLD positively or negatively regulate RIP1-/RIP3-dependent necroptosis by different mechanisms. Recent studies demonstrate the involvement of necroptosis in many neurological disorders including stroke, trauma, neonatal hypoxic–ischemic encephalopathy, and Huntington’s disease. As a potential therapeutic target, the understanding of necroptotic mechanisms will provide new insights to develop more potent neuroprotectants and specific therapeutic strategies for clinical treatments of neurological disorders.

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Abbreviations

AIF:

Apoptosis-inducing factor

ANT:

Adenine nucleotide translocase

Aur-A:

Aurora-A kinase

BHA:

Butylated hydroxyanisole

CCI:

Controlled cortical impact

cIAP1/2:

Apoptosis protein 1/2

CypA:

Cyclophilin A

CypD:

Cyclophilin D

DRP1:

Dynamin-related protein 1

FADD:

Fas-associated protein with death domain

FLIPL:

FLICE-like inhibitory protein long

GLUD1:

Glutamate dehydrogenase 1

GLUL:

Glutamate–ammonia ligase

HI:

Hypoxia–ischemia

HIE:

Hypoxic–ischemic encephalopathy

HMGB1:

High-mobility group box 1 protein

HSP90:

Heat shock protein

IAPs:

Inhibitors of apoptosis

MEFs:

Mouse embryonic fibroblasts

MKRN1:

Makorin Ring Finger Protein 1

MLKL:

Mixed lineage kinase domain-like protein

OGD:

Oxygen–glucose deprivation

Plk1:

Polo-like kinase 1

RHIM:

RIP homotypic interaction motif

RIP:

Receptor-interacting protein

ROS:

Reactive oxygen species

TNFR1:

TNF receptor 1

TNF-α:

Tumor necrosis factor-α

z-VAD:

z-VAD-fmk

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Acknowledgments

This chapter and related studies were supported by grants 30700245, 81071095, and 81120108011 from the National Natural Science Foundation of China (to XX) and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.

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Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou City, Jiangsu, China

    Jing Chen & Xingshun Xu

  2. The Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou City, Jiangsu, China

    Jing Chen & Xingshun Xu

  3. Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, 37614, TN, USA

    Richard M. Kostrzewa

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  1. Jing Chen
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  2. Richard M. Kostrzewa
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  3. Xingshun Xu
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Correspondence to Xingshun Xu .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

    Richard M. Kostrzewa

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Chen, J., Kostrzewa, R.M., Xu, X. (2014). Necroptosis, a Potential Therapeutic Target for Neurological Disorders. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_166

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