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://dx.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
Not SetBB ⁄ C008200 ⁄ 1 (CISBAN)BBSRC
Not SetBB ⁄ I020748 ⁄ 1BBSRC
Not SetG0601333MRC
Keywords: aging; brain; inflammation; oxidative stress; neurons; senescence
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 34587
Depositing User: Jill Saffrey
Date Deposited: 16 Oct 2012 15:19
Last Modified: 24 Apr 2014 17:57
URI: http://oro.open.ac.uk/id/eprint/34587
Share this page:

Actions (login may be required)

View Item
Report issue / request change

Policies | Disclaimer

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