The Open UniversitySkip to content
 

Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response

Jurk, Diana; Wang, Chunfang; Miwa, Satomi; Maddick, Mandy; Korolchuk, Viktor; Tsolou, Avgi; Gonos, Efstathios S.; Thrasivoulou, Christopher; Saffrey, M. Jill; Cameron, Kerry and von Zglinicki, Thomas (2012). Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell, 11(6) pp. 996–1004.

Full text available as:
[img]
Preview
PDF (Version of Record) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (1160Kb) | Preview
DOI (Digital Object Identifier) Link: http://doi.org/10.1111/j.1474-9726.2012.00870.x
Google Scholar: Look up in Google Scholar

Abstract

In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro-inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging. To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence like state in mature postmitotic neurons in vivo. About 40 80% of Purkinje neurons and 20–40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old C57Bl ⁄ 6 mice showed severe DNA damage, activated p38MAPkinase, high ROS production and oxidative damage, interleukin IL-6 production, heterochromatinization and senescence-associated b-galactosidase activity. Frequencies of these senescence-like neurons increased with age. Short term caloric restriction tended to decrease frequencies of positive cells. The phenotype was aggravated in brains of late-generation TERC) ⁄ ) mice with dysfunctional telomeres. It was fully rescued by loss of p21(CDKN1A) function in late- generation TERC) ⁄ )CDKN1A) ⁄ ) mice, indicating p21 as the necessary signal transducer between DNA damage response and senescence-like phenotype in neurons, as in senescing fibroblasts and other proliferation competent cells. We conclude that a senescence-like phenotype is possibly not restricted to proliferation-competent cells. Rather, dysfunctional telomeres and ⁄ or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence-like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.

Item Type: Journal Article
Copyright Holders: 2012 The Authors
ISSN: 1474-9726
Project Funding Details:
Funded Project NameProject IDFunding Body
CISBANBB/C008200/1BBSRC (Biotechnology and Biological Sciences Research Council)
Not SetBB/I020748/1BBSRC (Biotechnology and Biological Sciences Research Council)
Not SetG0601333MRC (Medical Research Council)
Keywords: aging; brain; inflammation; oxidative stress; neurons; senescence
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Science
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 34587
Depositing User: Jill Saffrey
Date Deposited: 16 Oct 2012 15:19
Last Modified: 29 Apr 2016 18:25
URI: http://oro.open.ac.uk/id/eprint/34587
Share this page:

Altmetrics

Scopus Citations

► Automated document suggestions from open access sources

Download history for this item

These details should be considered as only a guide to the number of downloads performed manually. Algorithmic methods have been applied in an attempt to remove automated downloads from the displayed statistics but no guarantee can be made as to the accuracy of the figures.

Actions (login may be required)

Policies | Disclaimer

© The Open University   + 44 (0)870 333 4340   general-enquiries@open.ac.uk