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.

KEYWORDS:

• Aging
• axonal degeneration
• necroptosis
• neurodegenerative diseases
• neuroprotection
• necroaxoptosis

Article Highlights

• Necroptosis is a recently identified mechanism of regulated cell death that can be activated by several stimuli including infection, inflammation, and activation of toll-like and cell death receptors. Necroptosis shares morphological and inflammatory features with non-regulated cell death by necrosis.

• The necroptosis pathway requires as a first step the kinase activity of the proteins RIPK1 and RIPK3 to form the necrosome complex. Upon MLKL recruitment to this complex, its activation might result in the formation of oligomers that translocate and permeabilize the plasma membrane triggering cell death.

• Although the necroptotic signaling pathway has crucial roles in development and tissue homeostasis, several reports have implicated necroptosis in the pathogenesis of numerous diseases, including various neurodegenerative conditions.

• Aging is the most important risk factor for neurodegenerative conditions; therefore, the increased aged population worldwide represents an important social and economic burden as currently there is no cure for age-related neurodegenerative diseases.

• Although the exact mechanisms of neurodegeneration in most neurodegenerative conditions are not clearly understood, recent evidence has demonstrated that necroptosis represents an important driver for neuronal loss in several of these diseases.

• Recently published data have implicated the necroptotic machinery in the mechanisms of axonal degeneration, and the term necroaxoptosis has been proposed to describe this process.

• Degeneration of the axon represents a common, early feature of neurodegenerative conditions that occurs before the destruction of the neuronal soma; thus, necroaxoptosis emerges as a novel target to treat neurodegenerative diseases before irreversible neuronal death occurs.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was funded by grants from Geroscience Center for Brain Health and Metabolism (FONDAP-15150012), Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, 1150766), MJ Fox foundation grant No. 17303 (to F Court) and Comisión Nacional de Investigación Científica y Tecnológica, Fondecyt de Postdoctorado Project 3180341 (to N Salvadores).