Toggle Main Menu Toggle Search

Open Access padlockePrints

The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?

Lookup NU author(s): Edward FielderORCiD, Professor Thomas von Zglinicki, Dr Diana Jurk

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

© 2017 - IOS Press and the authors. All rights reserved. Neurons are exposed to high levels of DNA damage from both physiological and pathological sources. Neurons are post-mitotic and their loss cannot be easily recovered from; to cope with DNA damage a complex pathway called the DNA damage response (DDR) has evolved. This recognizes the damage, and through kinases such as ataxia-telangiectasia mutated (ATM) recruits and activates downstream factors that mediate either apoptosis or survival. This choice between these opposing outcomes integrates many inputs primarily through a number of key cross-road proteins, including ATM, p53, and p21. Evidence of re-entry into the cell-cycle by neurons can be seen in aging and diseases such as Alzheimer's disease. This aberrant cell-cycle re-entry is lethal and can lead to the apoptotic death of the neuron. Many downstream factors of the DDR promote cell-cycle arrest in response to damage and appear to protect neurons from apoptotic death. However, neurons surviving with a persistently activated DDR show all the features known from cell senescence; including metabolic dysregulation, mitochondrial dysfunction, and the hyper-production of pro-oxidant, pro-inflammatory and matrix-remodeling factors. These cells, termed senescence-like neurons, can negatively influence the extracellular environment and may promote induction of the same phenotype in surrounding cells, as well as driving aging and age-related diseases. Recently developed interventions targeting the DDR and/or the senescent phenotype in a range of non-neuronal tissues are being reviewed as they might become of therapeutic interest in neurodegenerative diseases.


Publication metadata

Author(s): Fielder E, Von Zglinicki T, Jurk D

Publication type: Review

Publication status: Published

Journal: Journal of Alzheimer's Disease

Year: 2017

Volume: 60

Issue: s1

Pages: S107-S131

Online publication date: 15/09/2017

Acceptance date: 08/02/2017

ISSN (print): 1387-2877

ISSN (electronic): 1875-8908

Publisher: IOS Press

URL: https://doi.org/10.3233/JAD-161221

DOI: 10.3233/JAD-161221


Share