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Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology
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 excisi...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441048/ https://www.ncbi.nlm.nih.gov/pubmed/34496255 http://dx.doi.org/10.1016/j.celrep.2021.109668 |
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author | SenGupta, Tanima Palikaras, Konstantinos Esbensen, Ying Q. Konstantinidis, Georgios Galindo, Francisco Jose Naranjo Achanta, Kavya Kassahun, Henok Stavgiannoudaki, Ioanna Bohr, Vilhelm A. Akbari, Mansour Gaare, Johannes Tzoulis, Charalampos Tavernarakis, Nektarios Nilsen, Hilde |
author_facet | SenGupta, Tanima Palikaras, Konstantinos Esbensen, Ying Q. Konstantinidis, Georgios Galindo, Francisco Jose Naranjo Achanta, Kavya Kassahun, Henok Stavgiannoudaki, Ioanna Bohr, Vilhelm A. Akbari, Mansour Gaare, Johannes Tzoulis, Charalampos Tavernarakis, Nektarios Nilsen, Hilde |
author_sort | SenGupta, Tanima |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8441048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-84410482021-09-20 Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology SenGupta, Tanima Palikaras, Konstantinos Esbensen, Ying Q. Konstantinidis, Georgios Galindo, Francisco Jose Naranjo Achanta, Kavya Kassahun, Henok Stavgiannoudaki, Ioanna Bohr, Vilhelm A. Akbari, Mansour Gaare, Johannes Tzoulis, Charalampos Tavernarakis, Nektarios Nilsen, Hilde Cell Rep Article 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. Cell Press 2021-09-07 /pmc/articles/PMC8441048/ /pubmed/34496255 http://dx.doi.org/10.1016/j.celrep.2021.109668 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article SenGupta, Tanima Palikaras, Konstantinos Esbensen, Ying Q. Konstantinidis, Georgios Galindo, Francisco Jose Naranjo Achanta, Kavya Kassahun, Henok Stavgiannoudaki, Ioanna Bohr, Vilhelm A. Akbari, Mansour Gaare, Johannes Tzoulis, Charalampos Tavernarakis, Nektarios Nilsen, Hilde Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology |
title | Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology |
title_full | Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology |
title_fullStr | Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology |
title_full_unstemmed | Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology |
title_short | Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology |
title_sort | base excision repair causes age-dependent accumulation of single-stranded dna breaks that contribute to parkinson disease pathology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441048/ https://www.ncbi.nlm.nih.gov/pubmed/34496255 http://dx.doi.org/10.1016/j.celrep.2021.109668 |
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