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

Edward Fielder, Thomas Von Zglinicki, Diana Jurk

Research output: Contribution to journalReview article

24 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)S107-S131
JournalJournal of Alzheimer's Disease
Volume60
Issue numbers1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Keywords

  • Aging
  • apoptosis
  • cell senescence
  • DNA damage response
  • neurodegeneration

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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