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

Chiara Milanese, Silvia Cerri, Ayse Ulusoy, Simona V. Gornati, Audrey Plat, Sylvia Gabriels, Fabio Blandini, Donato A. Di Monte, Jan H. Hoeijmakers, Pier G. Mastroberardino

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Article number818
JournalCell Death and Disease
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

Fingerprint

DNA Damage
Parkinson Disease
alpha-Synuclein
DNA Repair
Poisons
Dopaminergic Neurons
DNA
Oxidants
Neurodegenerative Diseases
Quality Control
Reactive Oxygen Species
Chronic Disease
Phosphotransferases
Cell Culture Techniques
Antioxidants
Pathology
Injections

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Milanese, C., Cerri, S., Ulusoy, A., Gornati, S. V., Plat, A., Gabriels, S., ... Mastroberardino, P. G. (2018). Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease. Cell Death and Disease, 9(8), [818]. https://doi.org/10.1038/s41419-018-0848-7

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

In: Cell Death and Disease, Vol. 9, No. 8, 818, 01.08.2018.

Research output: Contribution to journalArticle

Milanese, C, Cerri, S, Ulusoy, A, Gornati, SV, Plat, A, Gabriels, S, Blandini, F, Di Monte, DA, Hoeijmakers, JH & Mastroberardino, PG 2018, 'Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease', Cell Death and Disease, vol. 9, no. 8, 818. https://doi.org/10.1038/s41419-018-0848-7
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. / Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease. In: Cell Death and Disease. 2018 ; Vol. 9, No. 8.
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