Abstract
Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor-interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM-containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL). RIP1 plays a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, and these functions are often cell type and context dependent. Increasing evidence suggests that necroptosis plays an important role in the pathogenesis of neurodegenerative diseases. Moreover, small molecules such as necrostatin-1 are thought inhibit necroptotic signaling pathway. Understanding the precise mechanisms underlying necroptosis and its interactions with other cell death pathways in neurodegenerative diseases could provide significant therapeutic insights. The present review is aimed at summarizing the molecular mechanisms of necroptosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases.
Highlights
Necroptosis can be widely stimulated by tumor necrosis factor (TNF), other members of the TNF death ligand family (Fas and TNF-related apoptosis-inducing ligand (TRAIL)), interferons, Toll-like receptors (TLRs) signaling and viral infection via the DNA sensor DNAdependent activator of interferon regulatory factor (DAI)
One of the best studied form of necroptotic cell death is initiated by tumor necrosis factor (TNF), but necroptosis can be induced by other members of the TNF death ligand family (Fas and TNF-related apoptosis-inducing ligand (TRAIL)), interferons (IFNs), Toll-like receptors (TLRs) signaling and viral infection via the DNA sensor DNAdependent activator of interferon regulatory factor (DAI).[3]
TNF activate TNF receptor 1 (TNFR1) through the pre-ligand assembly domain in the extracellular portion of TNFR1 and triggers the trimerization of TNFR1.13 This process, initiates the assembly of a transient molecular complex named complex I, which consists of TNFR1associated death domain protein (TRADD), TRAF2, cellular inhibitor of apoptosis protein 1/2 and RIP114,15 (Figure 2)
Summary
How to monitor necroptosis in the diagnosis and prognosis of neurodegenerative disease?. What are the relative contributions of necroptosis and other forms of programmed cell death to neurodegenerative disease?. Two forms of cell death have been recognized: necrosis and apoptosis. Apoptosis, which is characterized by apoptotic body formation, nuclear shrinkage and fragmentation, and membrane blebbing, had been researched as the main form of programmed cell death.[2] increasing studies have described a genetically programmed and regulated form of necrosis, termed necroptosis.[3,4]. Necroptosis resembles cellular necrosis, which is distinguished from apoptosis by the presence of clusters of dying cells, an early loss of plasma membrane integrity, cell and organelle swelling, granular cytoplasm, chromatin fragmentation, and cellular lysis.[10] In contrast to apoptosis, the cellular contents of necroptotic cells passively enter the extracellular matrix through the disrupted cell membrane.[10].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
