Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology
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- Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 109668 |
| Tidsskrift | Cell Reports |
| Vol/bind | 36 |
| Udgave nummer | 10 |
| ISSN | 2211-1247 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
We thank Natascia Ventura and Garry Wong for critical reading of the manuscript and insightful comments and A. Pasparaki for technical support. We thank David M Wilson III (Boost Scientific) and Miriam Sander (https://www.logicalflow.biz/) for input and manuscript editing. We thank R. Blakely for sharing the BY273 strain, B.P. Braeckman for the Hyper-expressing nematodes, and E.M. Jorgensen for C. elegans strain expressing mitochondria-targeted GFP and cytoplasmic mCherry in GABA motor neurons. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources of the National Institutes of Health. Mass spectrometry services were procured at PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, and Central Norway Regional Health Authority, Trondheim, Norway. This work was supported by the South East Norway Regional Health Authority (Grant no. 2015029). T.S. was supported by an institutional grant from Akershus University Hospital. K.P. is supported by an AXA Research Fund post-doctoral long-term fellowship, the Hellenic Foundation for Research and Innovation (HFRI), and the General Secretariat for Research and Technology (GSRT). K.A. is supported by a grant from Olav Thon foundation Norway (531811-710131). N.T. is funded by grants from the European Research Council (ERC ? GA695190 ? MANNA), the European Commission Framework Programmes, and the Greek Ministry of Education. J.G. and C.T. were supported by grants from The Research Council of Norway (288164, ES633272) and Bergen Research Foundation (BFS2017REK05). T.S. K.P. Y.Q.E. G.K. K.A. F.J.N.G. H.K. and I.S. conducted experiments, T.S. and K.P. wrote the manuscript, and H.N. designed the study, analyzed data, and wrote the manuscript. N.T. V.B. and M.A. edited the manuscript. The authors declare no competing interests.
Funding Information:
We thank Natascia Ventura and Garry Wong for critical reading of the manuscript and insightful comments and A. Pasparaki for technical support. We thank David M Wilson III (Boost Scientific) and Miriam Sander ( https://www.logicalflow.biz/ ) for input and manuscript editing. We thank R. Blakely for sharing the BY273 strain, B.P. Braeckman for the Hyper-expressing nematodes, and E.M. Jorgensen for C. elegans strain expressing mitochondria-targeted GFP and cytoplasmic mCherry in GABA motor neurons. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources of the National Institutes of Health. Mass spectrometry services were procured at PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, and Central Norway Regional Health Authority, Trondheim, Norway. This work was supported by the South East Norway Regional Health Authority (Grant no. 2015029 ). T.S. was supported by an institutional grant from Akershus University Hospital . K.P. is supported by an AXA Research Fund post-doctoral long-term fellowship , the Hellenic Foundation for Research and Innovation (HFRI), and the General Secretariat for Research and Technology (GSRT). K.A. is supported by a grant from Olav Thon foundation Norway ( 531811-710131 ). N.T. is funded by grants from the European Research Council ( ERC – GA695190 – MANNA ), the European Commission Framework Programmes , and the Greek Ministry of Education . J.G. and C.T. were supported by grants from The Research Council of Norway ( 288164 , ES633272 ) and Bergen Research Foundation ( BFS2017REK05 ).
Publisher Copyright:
© 2021 The Author(s)
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