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P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease

The transcription factor, p53, is critical for many important cellular functions involved in genome integrity, including cell cycle control, DNA damage response, and apoptosis. Disruption of p53 results in a wide range of disorders including cancer, metabolic diseases, and neurodegenerative diseases...

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Autores principales: Farmer, Kathleen M., Ghag, Gaurav, Puangmalai, Nicha, Montalbano, Mauro, Bhatt, Nemil, Kayed, Rakez
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418370/
https://www.ncbi.nlm.nih.gov/pubmed/32778161
http://dx.doi.org/10.1186/s40478-020-01012-6
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author Farmer, Kathleen M.
Ghag, Gaurav
Puangmalai, Nicha
Montalbano, Mauro
Bhatt, Nemil
Kayed, Rakez
author_facet Farmer, Kathleen M.
Ghag, Gaurav
Puangmalai, Nicha
Montalbano, Mauro
Bhatt, Nemil
Kayed, Rakez
author_sort Farmer, Kathleen M.
collection PubMed
description The transcription factor, p53, is critical for many important cellular functions involved in genome integrity, including cell cycle control, DNA damage response, and apoptosis. Disruption of p53 results in a wide range of disorders including cancer, metabolic diseases, and neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregates that contribute to disease pathology. Although p53 is known to aggregate, its propensity to aggregate in AD has never been assessed. Moreover, AD neuropathology includes lethal cell cycle re-entry, excessive DNA damage, and abnormal cell death which are all controlled by p53. Here, we show p53 forms oligomers and fibrils in human AD brain, but not control brain. p53 oligomers can also be detected in htau and P301L mouse models. Additionally, we demonstrate that p53 interacts with tau, specifically tau oligomers, in AD brain and can be recapitulated by in vitro exogenous tau oligomer treatment in C57BL/6 primary neurons. p53 oligomers also colocalize, potentially seeding, endogenous p53 in primary neurons. Lastly, we demonstrate that in the presence of DNA damage, phosphorylated p53 is mislocalized outside the nucleus and p53-mediated DNA damage responders are significantly decreased in AD brain. Control brain shows a healthy DNA damage response, indicating a loss of nuclear p53 function in AD may be due to p53 aggregation and/or interactions with tau oligomers. Given the critical role of p53 in cellular physiology, the disruption of this crucial transcription factor may set an irreversible course towards neurodegeneration in AD and potentially other tauopathies, warranting further investigation.
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spelling pubmed-74183702020-08-12 P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease Farmer, Kathleen M. Ghag, Gaurav Puangmalai, Nicha Montalbano, Mauro Bhatt, Nemil Kayed, Rakez Acta Neuropathol Commun Research The transcription factor, p53, is critical for many important cellular functions involved in genome integrity, including cell cycle control, DNA damage response, and apoptosis. Disruption of p53 results in a wide range of disorders including cancer, metabolic diseases, and neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregates that contribute to disease pathology. Although p53 is known to aggregate, its propensity to aggregate in AD has never been assessed. Moreover, AD neuropathology includes lethal cell cycle re-entry, excessive DNA damage, and abnormal cell death which are all controlled by p53. Here, we show p53 forms oligomers and fibrils in human AD brain, but not control brain. p53 oligomers can also be detected in htau and P301L mouse models. Additionally, we demonstrate that p53 interacts with tau, specifically tau oligomers, in AD brain and can be recapitulated by in vitro exogenous tau oligomer treatment in C57BL/6 primary neurons. p53 oligomers also colocalize, potentially seeding, endogenous p53 in primary neurons. Lastly, we demonstrate that in the presence of DNA damage, phosphorylated p53 is mislocalized outside the nucleus and p53-mediated DNA damage responders are significantly decreased in AD brain. Control brain shows a healthy DNA damage response, indicating a loss of nuclear p53 function in AD may be due to p53 aggregation and/or interactions with tau oligomers. Given the critical role of p53 in cellular physiology, the disruption of this crucial transcription factor may set an irreversible course towards neurodegeneration in AD and potentially other tauopathies, warranting further investigation. BioMed Central 2020-08-10 /pmc/articles/PMC7418370/ /pubmed/32778161 http://dx.doi.org/10.1186/s40478-020-01012-6 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Farmer, Kathleen M.
Ghag, Gaurav
Puangmalai, Nicha
Montalbano, Mauro
Bhatt, Nemil
Kayed, Rakez
P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
title P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
title_full P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
title_fullStr P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
title_full_unstemmed P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
title_short P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
title_sort p53 aggregation, interactions with tau, and impaired dna damage response in alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418370/
https://www.ncbi.nlm.nih.gov/pubmed/32778161
http://dx.doi.org/10.1186/s40478-020-01012-6
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