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 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.

Tau Oligomers Neurotoxicity

“…Tau oligomers can interact with p53, which is a transcription factor involved in many processes such as apoptosis [62], DNA damage repair [63], and cell cycle control [63]. Farmer et al [64] proved that the p53 protein and TauOs (recognized by the T22 antibody) interact in the neurons of AD patients and a mouse model associated with AD (Tg2576/Tau P301L). The evidences presented in the study by Farmer et al [64] suggest that the interaction between p53 and TauOs may be due to protein misfolding.…”

“…Farmer et al [64] proved that the p53 protein and TauOs (recognized by the T22 antibody) interact in the neurons of AD patients and a mouse model associated with AD (Tg2576/Tau P301L). The evidences presented in the study by Farmer et al [64] suggest that the interaction between p53 and TauOs may be due to protein misfolding. In the p53 molecule, the DNA-binding domains, the N-terminal domain and the C-terminal base domain, were in a state of intrinsic disorder [65,66] and therefore prone to misfolding.…”

“…Thus, the proximity of p53 and tau may increase the likelihood of p53 interaction with tau, also at an earlier stage of pathology, when TauOs are initially formed. The interaction of p53 and TauOs leading to the aggregation of both proteins inhibits nuclear import of the p53 and causes loss of its function of the transcription factor [64]. Lasagna-Reeves et al [69] showed that aggregated p53 cannot bind to DNA, confirming that aggregation leads to a loss of p53 function.…”

“…Moreover, the structure of the nuclear membrane and its pores can be affected by pathological forms of tau [70]. This may hinder p53 transport into the nucleus and cause its accumulation in the cytoplasm, which has been observed both in neurons of AD patients and tau overexpressing mice [64,71].…”

Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

“…Protein aggregation poses a threat to the integrity of the genome A growing body of experimental data points at protein aggregation as a possible cause of DNA damage. Aggregation of certain disease-associated proteins, including amyloid-β fragments and α-synuclein, has been associated with elevated levels of DNA strand breaks (Farmer et al 2020;Illuzzi et al 2009;Vasquez et al 2017), indicating that DNA damage can be an ancillary consequence of protein aggregation. Two primary biological cascades have been proposed to underlie this damage.…”