Necroptosis in neurodegenerative diseases: a potential therapeutic target

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.

Figure 1

Timeline for momentous events in the studies of necroptosis and its role in neurodegenerative diseases. Blue boxes represent the major findings in the discovery of necroptosis signaling pathway; yellow boxes highlight the research breakthroughs concerning the role of necroptosis in neurodegenerative disease

Figure 2

Necroptotic pathways. After TNF stimulation, TNFR1 recruits TRADD and RIP1 to complex I via their respective death domains. TRADD recruits cellular inhibitors of apoptosis (cIAPs), which ubiquitinate components of complex I. Deficient complex I activity, such as occurs with the deubiquitination of RIP1 by cylindromatosis (CYLD), can lead to the formation of the necrosome, which consist of FADD, procaspase-8, RIP1, RIP3, and MLKL. RIP1 interacts with FADD though death domain. Subsequently, procaspase-8, cFLIP_L and cFLIP_S are recruited to death receptor-bound FADD. Procaspase-8 homodimerization generate processed active caspase-8, which activates effector caspase cascade and induces apoptosis. Procaspase-8-cFLIP_L heterodimer does not process caspase-8 but cleaves RIP1, which leading to cellular survival. However, procaspase-8-cFLIP_S heterodimer fails to cleave RIP1, which allows the assembly of necrosome and the execution of necroptosis. In the necrosome, MLKL are phosphorylated and translocate to the plasma membrane, which leads to influx of Ca²⁺ or Na⁺ ions and direct pore formation with the release of cell damage-associated molecular patterns (cDAMPs) such as mitochondrial DNA (mtDNA), high-mobility group box 1 (HMGB1), interleukin (IL)-33, IL-1α, and ATP. zVAD, a pan-caspase inhibitors, inhibits caspases cascade and apoptosis. Nec-1 inhibits RIP1 kinase activity and necroptosis. NSA blocks necroptosis by preventing the membrane translocation of MLKL. Boxes around the cell model diagram represent the major pathogenesis of the neurodegenerative diseases in this review except ALS, of which the etiology remains unknown