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 open new avenues for understanding the mechanisms of neuronal loss in NDs, 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 activation of this pathway in the mechanism of axonal degeneration. We searched on PubMed the literature regarding necroptosis published between 2008 and 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.

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 open new avenues for understanding the mechanisms of neuronal loss in NDs, 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 activation of this pathway in the mechanism of axonal degeneration. We searched on PubMed the literature regarding necroptosis published between 2008 and 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.