P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
Abstract 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...
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-01012-6 |
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| author | Kathleen M. Farmer Gaurav Ghag Nicha Puangmalai Mauro Montalbano Nemil Bhatt Rakez Kayed |
| author_facet | Kathleen M. Farmer Gaurav Ghag Nicha Puangmalai Mauro Montalbano Nemil Bhatt Rakez Kayed |
| author_sort | Kathleen M. Farmer |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-13T23:17:37Z |
| format | Article |
| id | doaj.art-89d5269d42b94a85852128d51a041c5f |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-13T23:17:37Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-89d5269d42b94a85852128d51a041c5f2022-12-22T02:25:21ZengBMCActa Neuropathologica Communications2051-59602020-08-018112110.1186/s40478-020-01012-6P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s diseaseKathleen M. Farmer0Gaurav Ghag1Nicha Puangmalai2Mauro Montalbano3Nemil Bhatt4Rakez Kayed5Mitchell Center for Neurodegenerative Diseases, University of Texas Medical BranchMitchell Center for Neurodegenerative Diseases, University of Texas Medical BranchMitchell Center for Neurodegenerative Diseases, University of Texas Medical BranchMitchell Center for Neurodegenerative Diseases, University of Texas Medical BranchMitchell Center for Neurodegenerative Diseases, University of Texas Medical BranchMitchell Center for Neurodegenerative Diseases, University of Texas Medical BranchAbstract 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.http://link.springer.com/article/10.1186/s40478-020-01012-6p53TauOligomersDNA damageSeedingCross-seeding |
| spellingShingle | Kathleen M. Farmer Gaurav Ghag Nicha Puangmalai Mauro Montalbano Nemil Bhatt Rakez Kayed P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease Acta Neuropathologica Communications p53 Tau Oligomers DNA damage Seeding Cross-seeding |
| 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 | p53 Tau Oligomers DNA damage Seeding Cross-seeding |
| url | http://link.springer.com/article/10.1186/s40478-020-01012-6 |
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