The necroptosis pathway and its role in age-related neurodegenerative diseases: will it open up new therapeutic avenues in the next decade?

Abstract

Introduction: Necroptosis is a programmed form of necrotic cell death. Growing evidence demonstrates that necroptosis contributes to cell demise in different pathological conditions including age-dependent neurodegenerative diseases (NDs). These findings opened new avenues for understanding the mechanisms of neuronal loss in these diseases, which might eventually translate into novel therapeutic interventions. Areas covered: We reviewed key aspects of necroptosis, in health and disease, focusing on evidence demonstrating its involvement in the pathogenesis of age-related NDs. We then highlight the engagement of this pathway in the mechanism of axonal degeneration. We searched on PubMed the literature regarding necroptosis published between 2008-2020 and reviewed all publications were necroptosis was studied in the context of age-related NDs. Expert opinion: Axonal loss and neuronal death are the ultimate consequences of NDs that translate into disease phenotypes. Targeting degenerative mechanisms of the neuron appears as a strategy that might cover a wide range of diseases. Thus, the participation of necroptosis as a common mediator of neuronal demise emerges as a promising target for therapeutic intervention. Considering evidence demonstrating that necroptosis mediates axonal degeneration, we propose and discuss the potential of targeting necroptosis-mediated axonal destruction as a strategy to tackle NDs before neuronal loss occurs.