Post-translational Modifications of the p53 Protein and the Impact in Alzheimer’s Disease: A Review of the Literature<strong> </strong>

Abstract

Our understanding of Alzheimer&amp;rsquo;s disease (AD) pathogenesis has developed with several hypotheses over the last 40 years, including the Amyloid and Tau hypotheses, respectively. More recently, the p53 protein, well-known as &amp;lsquo;the guardian of the genome,&amp;rsquo; has gained attention for its role in the early evolution of AD. This is due to p53&amp;rsquo;s central role in the control of oxidative stress and potential involvement in both Amyloid and Tau pathways. p53 is commonly regulated by post-translational modifications (PTMs), which affect its conformation, increasing its capacity to adopt multiple structural and functional states, including those that can influence several processes in AD. The following review will explore the impact of p53 post-translational modifications (PTMs) on its function and consequential involvement in AD pathogenesis.

The function of p53 and its role in Alzheimer’s and Parkinson’s disease compared to age-related macular degeneration

“…The two reactions are again in response to cellular stress and are facilitated by the ubiquitination-proteasome system as well as proteins of the small ubiquitin-like modifier family (SUMO) ( Seeler and Dejean, 2003 ; Li et al, 2022 ). Besides the four named PTMs, numerous other protein modifications exist which again lead to changes of p53-functioning ( Clark et al, 2022 ).…”

“…The thereby observed and later named “unfolded p53” protein comprises structural aberrations which can be induced through various influences. In the review of Clark et al, different factors, like reactive oxygen species (ROS), reactive nitrogen species (RNS), Aβ-amyloid or metallothionein are listed which lead to the unfolded p53 modification in context of AD pathogenesis ( Clark et al, 2022 ). Since under its normal composition, p53 controls many processes in the cell in order to avoid cellular damages, the emergence of unfolded p53 subsequently initiates abnormal regulations like the inhibition of the SOD and GAP-43 pathway or the promotion of the CD44 and mTOR pathway, overall leading to neuronal dysfunction and the promotion of neurodegeneration ( Abate et al, 2020 ).…”

Identification of Kv4.2 protein complex and modifications by tandem affinity purification-mass spectrometry in primary neurons

“…Post-translational modifications (PTMs) have a strong impact on proteins across all kingdoms of life, affecting multiple functional and chemical properties of their protein recipients. Dysregulations in PTMs have been implicated in various dysfunctions and diseases (Clark et al, 2022;Yoo et al, 2022). The expression and modification of synaptic proteins are dynamically regulated, depending on the neuronal activity, which underlies synaptic plasticity (Malenka and Bear, 2004).…”