In Silico Phosphoproteomic Analysis Reveals Divergent Regulation of Presenilin 1 and Presenilin 2

TL;DR

This study uses computational analysis to uncover differences in how Presenilin 1 and 2 are regulated through phosphorylation, which could impact Alzheimer's disease research.

Contribution

The study reveals novel divergent phosphorylation patterns of Presenilin 1 and 2, offering new insights into their regulation.

Findings

Presenilin 1 and 2 show distinct phosphorylation patterns.

These differences suggest unique regulatory mechanisms for each protein.

The findings may influence drug discovery targeting the gamma secretase complex.

Abstract

The Presenilins are multi-pass transmembrane proteins that form part of the multi-protein gamma secretase complex. The hydrolytic activity of the gamma secretase complex is responsible for the cleavage of a wide range of substrates, including the amyloid precursor protein (APP) – a proteolytic event that is the final step in the production of the amyloid beta peptide, a protein fragment deposited in the brains of individuals with Alzheimer’s disease (AD). Both PSEN1 and PSEN2, the genes encoding the Presenilins, are mutated in familial AD, generating intense interest in the activity and function of these proteins. Despite this attention, the post-translational modification and regulation of the Presenilins is poorly understood. In order to address this gap in our knowledge, a bioinformatic approach was taken to examine the extant evidence for Presenilin phosphorylation. Derived from the Phosphosite repository, these data reveal divergent patterns of phosphorylation across Presenilin 1 and 2, highlighting distinct regulatory pathways that have implications for our understanding of the biology of these proteins, gamma secretase, and drug discovery targeting this complex.

The online version contains supplementary material available at 10.1007/s12017-026-08906-z.

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