Necroptosis: a regulated cell death pathway and potential therapeutic target in neurodegenerative disorders

Abstract

Necroptosis is a programmed cell death characterized by damage to the plasma membrane, secretion of cytoplasmic content, and inflammation induction. Recent findings suggest that the pathogenesis of tissue injuries associated with dysregulation of necroptosis signaling contributes significantly to the onset of neurodegenerative diseases. The canonical necroptosis signaling pathway includes the activation of receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1 and RIPK3) and the function of the mixed lineage kinase domain-like protein (MLKL). The dysregulation of such signaling results in neuronal and glial injuries and increased inflammation. Abnormalities of the necroptosis signaling have been demonstrated in many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. The manipulation of the RIPK1, RIPK3, and MLKL expression using pharmaceutical agents has shown positive results in the treatment of such diseases. However, the importance of necroptosis in physiological processes and protection against infections cannot be overestimated. This editorial emphasizes the relevance of necroptosis in neurodegenerative disease pathology and its potential as a pharmacological target. Difficulties associated with translating research into clinical application in the realm of pharmaceutical interventions are also discussed. Additional research in regulation of signaling pathways, disease mechanisms, timing, and safety of the necroptosis inhibitors may lead to novel treatments for neurodegenerative diseases.