Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology

Research output: Contribution to journalJournal articleResearchpeer-review

  • Tanima SenGupta
  • Konstantinos Palikaras
  • Ying Q. Esbensen
  • Georgios Konstantinidis
  • Francisco Jose Naranjo Galindo
  • Kavya Achanta
  • Henok Kassahun
  • Ioanna Stavgiannoudaki
  • Bohr, Vilhelm
  • Mansour Akbari
  • Johannes Gaare
  • Charalampos Tzoulis
  • Nektarios Tavernarakis
  • Hilde Nilsen

Aging, genomic stress, and mitochondrial dysfunction are risk factors for neurodegenerative pathologies, such as Parkinson disease (PD). Although genomic instability is associated with aging and mitochondrial impairment, the underlying mechanisms are poorly understood. Here, we show that base excision repair generates genomic stress, promoting age-related neurodegeneration in a Caenorhabditis elegans PD model. A physiological level of NTH-1 DNA glycosylase mediates mitochondrial and nuclear genomic instability, which promote degeneration of dopaminergic neurons in older nematodes. Conversely, NTH-1 deficiency protects against α-synuclein-induced neurotoxicity, maintaining neuronal function with age. This apparent paradox is caused by modulation of mitochondrial transcription in NTH-1-deficient cells, and this modulation activates LMD-3, JNK-1, and SKN-1 and induces mitohormesis. The dependance of neuroprotection on mitochondrial transcription highlights the integration of BER and transcription regulation during physiological aging. Finally, whole-exome sequencing of genomic DNA from patients with idiopathic PD suggests that base excision repair might modulate susceptibility to PD in humans.

Original languageEnglish
Article number109668
JournalCell Reports
Volume36
Issue number10
ISSN2211-1247
DOIs
Publication statusPublished - 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

    Research areas

  • aging, base excision repair, C. elegans, DNA-glycosylase, hydrogen peroxide, mitohormesis, neurodegeneration, NTH-1, oxidative DNA damage, Parkinson disease

ID: 280070244