p53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer's Disease

dc.creatorFarmer, Kathleen M
dc.date.accessioned2023-12-05T15:20:55Z
dc.date.available2023-12-05T15:20:55Z
dc.date.created2020-08
dc.date.issuedAugust 2020
dc.date.submittedAugust 2020
dc.date.updated2023-12-05T15:20:56Z
dc.description.abstractThe 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, P301L, and Tg2576 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. 
dc.format.mimetypeapplication/pdf
dc.identifier.uri
dc.identifier.urihttps://hdl.handle.net/2152.3/12200
dc.subjectBiology, Neuroscience
dc.subject.otherp53
dc.subject.othertau
dc.subject.otheroligomers
dc.subject.otherDNA damage
dc.subject.otherseeding
dc.subject.othercross-seeding
dc.subject.otherAlzheimer’s disease
dc.titlep53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer's Disease
dc.typeThesis
dc.type.materialtext
local.embargo.lift08/01/2023
local.embargo.terms08/01/2023
thesis.degree.departmentNeuroscience
thesis.degree.grantorThe University of Texas Medical Branch at Galveston
thesis.degree.nameNeuroscience (Doctoral)

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