Biology subjects

Fraser, P. E.

Publications and source records attributed to Fraser, P. E..

2 recordsLinked to original sources

bioRxiv2023

Quantitative Comparison of Presenilin Protein Expression Reveals Greater Activity of PS2-gamma-Secretase.

{gamma}-Secretase processing of APP has long been of interest in the pathological progression of Alzheimers disease (AD) due to its role in the generation of amyloid-{beta}. The catalytic component of the enzyme are 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-{gamma}-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 direct comparison of PS protein 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 and 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-{gamma}-secretase, PS2-{gamma}-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.

cell biology↗

bioRxiv2022

SUMO2 Protects Against Tau-induced Synaptic and Cognitive Dysfunction

Abnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimers disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD), which can be caused by mutations of Tau. Mutated and pathological Tau can undergo a range of post-translational modifications (PTMs) that might trigger or modulate disease pathology. Recent studies indicate that modification of wild type Tau by Small ubiquitin-like modifier SUMO isoform 1 (SUMO1) controls Tau hyperphosphorylation and aggregation, suggesting that SUMOylation acts as a central regulator of Taus biochemical properties. Besides SUMO1, Tau is modified by SUMO2/3, however the consequences of this modification have not been investigated. Here, using viral approaches on primary hippocampal neurons, transgenic mice expressing mutant Tau and SUMO2, and iPSC-derived neurons from FTD patients, we evaluated whether SUMO2/3 conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant Tau P301L, P301S, and R406W variants. We found that mutant forms of Tau are targets of SUMO2/3, and SUMO2/3 conjugation is neuroprotective. Importantly, expression of mutant Tau is accompanied by a significant reduction of SUMO2/3 conjugation levels, and restoring levels of SUMO2 reduces mutant Tau aggregation and phosphorylation in all model systems Furthermore, overexpression of SUMO2 restores levels of pre- and post-synaptic markers, associated with a complete rescue of the LTP and memory deficits in transgenic mice expressing mutant Tau. These findings bring to light the potential therapeutic implication of manipulating SUMO conjugation to detoxify Tau through PTM-based approaches.

neuroscience↗