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

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

doi:10.1016/j.celrep.2021.109668

Abstract

SummaryAging, 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.

Highlights

Parkinson disease (PD) is the second most common neurodegenerative disorder in humans
We found that incomplete repair of endogenous DNA base damage via NTH-1-initiated Base excision repair (BER) in both mitochondrial and nuclear DNA generates genomic stress during aging
The results show that DA neurons in nth-1;BY273 mutants were more resistant to 6-OHDA- and MPP+-induced neurotoxicity than DA neurons in BY273 animals (Figure 1E; Figure S1B)

Summary

Introduction

Parkinson disease (PD) is the second most common neurodegenerative disorder in humans. Clinical diagnosis of PD is based on observation of motor function defects along with significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. Neurodegeneration in PD is not restricted to these neurons, they are especially sensitive. All neurons are vulnerable to aging and oxidative stress, because of their high energy demand, intensive metabolism, and production of high levels of endogenous reactive oxygen species (ROS) (Camandola and Mattson, 2017). PD neurons experience oxidative stress that can damage cellular macromolecules, including DNA (Barzilai et al, 2017). Consistent with this, the genomic stress marker gH2AX is seen in neuronal cells from human PD patients (Sepe et al, 2016). The cause of aging-associated genomic stress in neurons remains elusive

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