Quantitative comparison of presenilin protein expression reveals greater activity of PS2-γ-secretase
Document Type
Journal Article
Publication Title
FASEB Journal
Volume
38
Issue
1
PubMed ID
38156414
Publisher
Wiley
School
School of Medical and Health Sciences
RAS ID
64692
Funders
Dementia Australia Research Foundation
Abstract
γ-secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid- . The catalytic component of the enzyme is the presenilins of which there are two homologues, Presenilin-1 (PS1) and Presenilin-2 (PS2). The field has focussed on the PS1 form of this enzyme, as it is typically considered the more active at APP processing. However, much of this work has been completed without appropriate consideration of the specific levels of protein expression of PS1 and PS2. We propose that expression is an important factor in PS1- and PS2- -secretase activity, and that when this is considered, PS1 does not have greater activity than PS2. We developed and validated tools for quantitative assessment of PS1 and PS2 protein expression levels to enable the direct comparison of PS in exogenous and endogenous expression systems, in HEK-293 PS1 and/or PS2 knockout cells. We show that exogenous expression of Myc-PS1-NTF is 5.5-times higher than Myc-PS2-NTF. Quantitating endogenous PS protein levels, using a novel PS1/2 fusion standard we developed, showed similar results. When the marked difference in PS1 and PS2 protein levels is considered, we show that compared to PS1- -secretase, PS2- -secretase has equal or more activity on APP and Notch1. This study has implications for understanding the PS1- and PS2-specific contributions to substrate processing, and their potential influence in AD pathogenesis.
DOI
10.1096/fj.202300954RR
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Comments
Eccles, M. K., Main, N., Carlessi, R., Armstrong, A. M., Sabale, M., Roberts-Mok, B., . . . Verdile, G. (2024). Quantitative comparison of presenilin protein expression reveals greater activity of PS2-γ-secretase. FASEB Journal, 38(1), article e23396. https://doi.org/10.1096/fj.202300954RR