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Cited by 119Parkinson's Disease Mechanisms and TreatmentsDNA Repair MechanismsNuclear Receptors and Signaling

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Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease

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Milanese, Chiara, Cerri, Silvia, Ulusoy, Ayse, Gornati, Simona V., Plat, Audrey, Gabriels, Sylvia, Blandini, Fabio, Di Monte, Donato A., Hoeijmakers, Jan H., Mastroberardino, Pier G.·2018·Cell Death & Disease
DOI 10.1038/s41419-018-0848-7PMC PMC6062587
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Abstract

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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Fig. 1 α-Synuclein overexpression or intracerebral seeding impacts the dopaminergic system. a–c Intranigral injection of AAV2/6 serotype expressing human α-syn (h-syn) results in increased protein expression paralleled by reduction in tyrosine hydroxylase (TH) levels. (d) h-syn is also expressed in dopaminergic cell bodies (arrows). e Unbiased stereological counts demonstrate a reduction in nigral dopaminergic cell bodies. f, g Intracranial injection of α-syn pre-formed fibrils (PFF) causes striatal dopaminergic denervation as evidenced by a reduction in TH immunoreactivity. h Increased levels of ser129-phosphosynuclein in the substantia nigra (arrows) indicate α-syn stress in PFF injected animals. i Unbiased stereological counts showing a decrease in dopaminergic cell bodies in the substantia nigra. Scale bars: 1 mm in a, b 50 μm in d. (**p < 0.01; ***p < 0.001; Student’s t test). All bar graphs show mean + /− s.e.m
Fig. 1 α-Synuclein overexpression or intracerebral seeding impacts the dopaminergic system. a–c Intranigral injection of AAV2/6 serotype expressing human α-syn (h-syn) results in increased protein expression paralleled by reduction in tyrosine hydroxylase (TH) levels. (d) h-syn is also expressed in dopaminergic cell bodies (arrows). e Unbiased stereological counts demonstrate a reduction in nigral dopaminergic cell bodies. f, g Intracranial injection of α-syn pre-formed fibrils (PFF) causes striatal dopaminergic denervation as evidenced by a reduction in TH immunoreactivity. h Increased levels of ser129-phosphosynuclein in the substantia nigra (arrows) indicate α-syn stress in PFF injected animals. i Unbiased stereological counts showing a decrease in dopaminergic cell bodies in the substantia nigra. Scale bars: 1 mm in a, b 50 μm in d. (**p < 0.01; ***p < 0.001; Student’s t test). All bar graphs show mean + /− s.e.mCC BY · PubMed Central
Fig. 2 Activation of the DDR in mice transduced with AAV2/6 h-syn. a h-syn expression increases 53BP1 and γH2AX foci, and ATM phosphorylation in nigral dopaminergic neurons. b The DDR is not activated by viral delivery of GFP. Scale bar: 50 μm. (**p < 0.01; ***p < 0.001; Student’s t test). All bar graphs show mean + /− s.e.m
Fig. 2 Activation of the DDR in mice transduced with AAV2/6 h-syn. a h-syn expression increases 53BP1 and γH2AX foci, and ATM phosphorylation in nigral dopaminergic neurons. b The DDR is not activated by viral delivery of GFP. Scale bar: 50 μm. (**p < 0.01; ***p < 0.001; Student’s t test). All bar graphs show mean + /− s.e.mCC BY · PubMed Central
Fig. 3 Activation of the DDR in mice injected with α-syn PFF in the striatum. Augmented levels 53BP1 and γH2AX foci, and ATM phosphorylation in dopamine neurons of the substantia nigra. Scale bar: 50 μm. (**p < 0.01; ***p < 0.001; Student’s t test). All bar graphs show mean + /− s.e.m
Fig. 3 Activation of the DDR in mice injected with α-syn PFF in the striatum. Augmented levels 53BP1 and γH2AX foci, and ATM phosphorylation in dopamine neurons of the substantia nigra. Scale bar: 50 μm. (**p < 0.01; ***p < 0.001; Student’s t test). All bar graphs show mean + /− s.e.mCC BY · PubMed Central
Fig. 4 Pro-oxidant species contribute to α-syn-mediated activation of the DDR. a, b Administration of the antioxidant NAC mitigates formation of PFF-mediated γH2AX and 53BP1 foci in differentiated SH-SY5Y cells. c Administration of the nitric oxide donor nitrite, which activates the endogenous antioxidant Nrf2 pathway, reduces formation of PFF-mediated γH2AX foci. Scale bars: 50 μm. (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001; one-way ANOVA followed by Dunnet’s multiple comparison post doc test.) All bar graphs show mean + /- s.e.m
Fig. 4 Pro-oxidant species contribute to α-syn-mediated activation of the DDR. a, b Administration of the antioxidant NAC mitigates formation of PFF-mediated γH2AX and 53BP1 foci in differentiated SH-SY5Y cells. c Administration of the nitric oxide donor nitrite, which activates the endogenous antioxidant Nrf2 pathway, reduces formation of PFF-mediated γH2AX foci. Scale bars: 50 μm. (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001; one-way ANOVA followed by Dunnet’s multiple comparison post doc test.) All bar graphs show mean + /- s.e.mCC BY · PubMed Central
Fig. 5 Potentiation of exogenous or endogenous antioxidants reverses mitochondrial anomalies induced by PFF in SH-SY5Y cells. a Representative trace of a microscale oxygraphy experiment. b NAC or c nitrite treatments restore basal and rotenone sensitive respiration, as well as reserve capacity in SH-SY5Y cells exposed to PFF. (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001; one-way ANOVA followed by Dunnet’s multiple comparison post doc test.) Graphs represent mean ± s.e.m
Fig. 5 Potentiation of exogenous or endogenous antioxidants reverses mitochondrial anomalies induced by PFF in SH-SY5Y cells. a Representative trace of a microscale oxygraphy experiment. b NAC or c nitrite treatments restore basal and rotenone sensitive respiration, as well as reserve capacity in SH-SY5Y cells exposed to PFF. (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001; one-way ANOVA followed by Dunnet’s multiple comparison post doc test.) Graphs represent mean ± s.e.mCC BY · PubMed Central
Fig. 6 Schematic illustrating the proposed model in which proteotoxic stress and DNA damage accumulation synergize to trigger an escalating positive feedback loop. α-Synuclein proteotoxicity impacts genomic integrity, which in turn promotes α-synuclein stress. α-synuclein-mediated DNA damage involves, but is not limited to the participation of mitochondrial pro-oxidant species, and other factors may contribute to α-synuclein-mediated DNA damage. The mechanisms that cause α-synuclein stress following DNA damage are unknown.
Fig. 6 Schematic illustrating the proposed model in which proteotoxic stress and DNA damage accumulation synergize to trigger an escalating positive feedback loop. α-Synuclein proteotoxicity impacts genomic integrity, which in turn promotes α-synuclein stress. α-synuclein-mediated DNA damage involves, but is not limited to the participation of mitochondrial pro-oxidant species, and other factors may contribute to α-synuclein-mediated DNA damage. The mechanisms that cause α-synuclein stress following DNA damage are unknown.CC BY · PubMed Central

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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
Publisher
Springer Science and Business Media LLC
Published
2018-07-26
Volume
9
Issue
8
Pages
818-818
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-018-0848-7
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
Licence
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 › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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