Necroptosis, a Potential Therapeutic Target for Neurological Disorders
Document Type
Book Contribution
Publication Date
1-1-2014
Description
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-a 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-a (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.
Citation Information
Chen, Jing; Kostrzewa, Richard M.; and Xu, Xingshun. 2014. Necroptosis, a Potential Therapeutic Target for Neurological Disorders. Handbook of Neurotoxicity. Vol.1 69-93. https://doi.org/10.1007/978-1-4614-5836-4_166 ISBN: 9781461458364,9781461458357