Cargando…
Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response
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 declin...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533793/ https://www.ncbi.nlm.nih.gov/pubmed/22882466 http://dx.doi.org/10.1111/j.1474-9726.2012.00870.x |
_version_ | 1782254457548963840 |
---|---|
author | Jurk, Diana Wang, Chunfang Miwa, Satomi Maddick, Mandy Korolchuk, Viktor Tsolou, Avgi Gonos, Efstathios S Thrasivoulou, Christopher Jill Saffrey, M Cameron, Kerry von Zglinicki, Thomas |
author_facet | Jurk, Diana Wang, Chunfang Miwa, Satomi Maddick, Mandy Korolchuk, Viktor Tsolou, Avgi Gonos, Efstathios S Thrasivoulou, Christopher Jill Saffrey, M Cameron, Kerry von Zglinicki, Thomas |
author_sort | Jurk, Diana |
collection | PubMed |
description | 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 β-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. |
format | Online Article Text |
id | pubmed-3533793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-35337932013-01-08 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 Jill Saffrey, M Cameron, Kerry von Zglinicki, Thomas Aging Cell Original Articles 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 β-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. Blackwell Publishing Ltd 2012-12 /pmc/articles/PMC3533793/ /pubmed/22882466 http://dx.doi.org/10.1111/j.1474-9726.2012.00870.x Text en © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Original Articles Jurk, Diana Wang, Chunfang Miwa, Satomi Maddick, Mandy Korolchuk, Viktor Tsolou, Avgi Gonos, Efstathios S Thrasivoulou, Christopher Jill Saffrey, M Cameron, Kerry von Zglinicki, Thomas Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response |
title | Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response |
title_full | Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response |
title_fullStr | Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response |
title_full_unstemmed | Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response |
title_short | Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response |
title_sort | postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a dna damage response |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533793/ https://www.ncbi.nlm.nih.gov/pubmed/22882466 http://dx.doi.org/10.1111/j.1474-9726.2012.00870.x |
work_keys_str_mv | AT jurkdiana postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT wangchunfang postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT miwasatomi postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT maddickmandy postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT korolchukviktor postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT tsolouavgi postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT gonosefstathioss postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT thrasivoulouchristopher postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT jillsaffreym postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT cameronkerry postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse AT vonzglinickithomas postmitoticneuronsdevelopap21dependentsenescencelikephenotypedrivenbyadnadamageresponse |