Role of Necroptosis in Central Nervous System Diseases

Abstract

Necroptosis is a type of precisely regulated necrotic cell death activated in caspase-deficient conditions. Multiple factors initiate the necroptotic signaling pathway, including toll-like receptor 3/4, tumor necrosis factor (TNF), dsRNA viruses, and T cell receptors. Presently, TNF-induced necroptosis via the phosphorylation of three key proteins, receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein, is the best-characterized process. Necroptosis induced by Z-DNA-binding protein 1 (ZBP-1) and toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon (TRIF) plays a significant role in infectious diseases, such as influenza A virus, Zika virus, and herpesvirus infection. An increasing number of studies have demonstrated the close association of necroptosis with multiple diseases, and disrupting necroptosis has been confirmed to be effective for treating (or managing) these diseases. The central nervous system (CNS) exhibits unique physiological structures and immune characteristics. Necroptosis may occur without the sequential activation of signal proteins, and the necroptosis of supporting cells has more important implications in disease development. Additionally, necroptotic signals can be activated in the absence of necroptosis. Here, we summarize the role of necroptosis and its signal proteins in CNS diseases and characterize typical necroptosis regulators to provide a basis for the further development of therapeutic strategies for treating such diseases. In the present review, relevant information has been consolidated from recent studies (from 2010 until the present), excluding the patents in this field.

Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway

“…It is reported that necroptosis, a new form of regulated cell deaths (RCDs), plays a role in the pathogenesis of ALI/ARDS. ,, Necroptosis, first defined by Yuan group, can be activated in a wide range of human inflammatory-involved diseases. − Mechanism of necroptosis has been relatively clear by numerous efforts in the past 2 decades . Various death receptors, such as TNF receptor-1 (TNFR1), CD95 (Fas), interferons (IFNs), and IFN-induced Z-DNA binding protein 1 (ZBP1), could initiate necroptosis pathway. − Briefly exemplified by TNFR1, tumor necrosis factor-α (TNF-α) interacts with TNFR1 to form signaling complex I on the membrane .…”

Defective lysosomal acidification contributes to TNFR1 mediated neuronal necroptosis in Alzheimer’s disease

“…One of the key inflammatory mediators under neurodegenerative condition is the soluble tumor necrosis factor (TNF) that primarily acts through binding TNF receptor 1 (TNFR1) and activating downstream signaling, including cell death pathways [7]. There is also growing evidence that TNFR1 signaling is implicated in multiple neurodegenerative conditions [8], including AD [9], Parkinson’s disease [10], and multiple sclerosis [11].…”