Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease
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The involvement of DNA damage and repair in aging processes is well established. Aging is an unequivocal risk factor for chronic neurodegenerative diseases, underscoring the relevance of investigations into the role that DNA alterations may have in the pathogenesis of these diseases. Consistently, even moderate impairment of DNA repair systems facilitates the onset of pathological features typical of PD that include derangement of the dopaminergic system, mitochondrial dysfunction, and alpha-synuclein stress. The latter establishes a connection between reduced DNA repair capacity and a cardinal feature of PD, alpha-synuclein pathology. It remains to be determined, however, whether alpha-synuclein stress activates in vivo the canonical signaling cascade associated with DNA damage, which is centered on the kinase ATM and substrates such as γH2Ax and 53BP1. Addressing these issues would shed light on age-related mechanisms impinging upon PD pathogenesis and neurodegeneration in particular. We analyzed two different synucleinopathy PD mouse models based either on intranigral delivery of AAV-expressing human alpha-synuclein, or intrastriatal injection of human alpha-synuclein pre-formed fibrils. In both cases, we detected a significant increase in γH2AX and 53BP1 foci, and in phospho-ATM immunoreactivity in dopaminergic neurons, which collectively indicate DNA damage and activation of the DNA damage response. Mechanistic experiments in cell cultures indicate that activation of the DNA damage response is caused, at least in part, by pro-oxidant species because it is prevented by exogenous or endogenous antioxidants, which also rescue mitochondrial anomalies caused by proteotoxic alpha-synuclein. These in vivo and in vitro findings reveal that the cellular stress mediated by alpha-synuclein—a pathological hallmark in PD—elicits DNA damage and activates the DNA damage response. The toxic cascade leading to DNA damage involves oxidant stress and mitochondrial dysfunction The data underscore the importance of DNA quality control for preservation of neuronal integrity and protection against neurodegenerative processes.
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Toxic aggregation of α-synuclein in the nucleus or cytosol elicits the accumulation of DSBs.
“However, toxic aggregation of α‐synuclein in the nucleus or cytosol elicits the accumulation of DSBs (Vasquez et al, 2017; Milanese et al, 2018).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Milanese et al, 2018
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- Authors
- Milanese, C., Cerri, S., Ulusoy, A., Gornati, S. V., Plat, A., Gabriels, S., Blandini, F., Di Monte, D. A., Hoeijmakers, J. H., & Mastroberardino, P. G.
- Affiliations
- Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
- Erasmus MC (NL)
- University of Cologne (DE)
- Corresponding author
- Mastroberardino, Pier G.
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2018-07-26
- Volume
- 9
- Issue
- 8
- Pages
- 818-818
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6062587
- OpenAlex
- W2883768767
- Cited by
- 118
- References
- 50
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 14 · 2023: 13 · 2022: 19 · 2021: 16 · 2020: 15 · 2019: 16 · 2018: 1
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion, cc-by-nc-nd)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DZNE Pub (submittedVersion, cc-by)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (Target Advancement Program)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, DNA damage response, alpha-synuclein, synucleinopathies, ATM kinase, γH2AX, 53BP1, oxidative stress, mitochondrial dysfunction, dopaminergic neurons, neurodegeneration, DNA repair, antioxidants, mouse model
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Animals, Disease Models, Animal, DNA Damage, DNA Repair, Histones, Humans, Mice, Inbred C57BL, Mitochondria, Parkinson Disease, Substantia Nigra, Reactive Oxygen Species, Cell Line, Tumor, Mice, alpha-Synuclein, Dopaminergic Neurons, Ataxia Telangiectasia Mutated Proteins
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