Milanese, Chiara ORCID: 0000-0001-8696-2603, Cerri, Silvia, Ulusoy, Ayse ORCID: 0000-0003-2840-3429, Gornati, Simona V., Plat, Audrey, Gabriels, Sylvia, Blandini, Fabio ORCID: 0000-0002-0178-1289, Di Monte, Donato A., Hoeijmakers, Jan H. and Mastroberardino, Pier G. (2018). Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson's disease. Cell Death Dis., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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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 gamma H2Ax 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 gamma H2AX 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Milanese, ChiaraUNSPECIFIEDorcid.org/0000-0001-8696-2603UNSPECIFIED
Cerri, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ulusoy, AyseUNSPECIFIEDorcid.org/0000-0003-2840-3429UNSPECIFIED
Gornati, Simona V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plat, AudreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabriels, SylviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blandini, FabioUNSPECIFIEDorcid.org/0000-0002-0178-1289UNSPECIFIED
Di Monte, Donato A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoeijmakers, Jan H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mastroberardino, Pier G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-179499
DOI: 10.1038/s41419-018-0848-7
Journal or Publication Title: Cell Death Dis.
Volume: 9
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-4889
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UNBIASED STEREOLOGICAL ESTIMATION; NUCLEOTIDE EXCISION-REPAIR; SUBSTANTIA-NIGRA NEURONS; ALPHA-SYNUCLEIN; DOPAMINERGIC-NEURONS; NEURODEGENERATION; STRESS; HIPPOCAMPUS; IMPAIRMENT; CHECKPOINTMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17949

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