TY - JOUR

T1 - Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology

AU - SenGupta, Tanima

AU - Palikaras, Konstantinos

AU - Esbensen, Ying Q.

AU - Konstantinidis, Georgios

AU - Galindo, Francisco Jose Naranjo

AU - Achanta, Kavya

AU - Kassahun, Henok

AU - Stavgiannoudaki, Ioanna

AU - Bohr, Vilhelm A.

AU - Akbari, Mansour

AU - Gaare, Johannes

AU - Tzoulis, Charalampos

AU - Tavernarakis, Nektarios

AU - Nilsen, Hilde

N1 - Publisher Copyright: © 2021 The Author(s)

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - aging

KW - base excision repair

KW - C. elegans

KW - DNA-glycosylase

KW - hydrogen peroxide

KW - mitohormesis

KW - neurodegeneration

KW - NTH-1

KW - oxidative DNA damage

KW - Parkinson disease

U2 - 10.1016/j.celrep.2021.109668

DO - 10.1016/j.celrep.2021.109668

M3 - Journal article

C2 - 34496255

AN - SCOPUS:85114245627

VL - 36

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 10

M1 - 109668

ER -