Biology subjects

Groth, D.

Publications and source records attributed to Groth, D..

3 recordsLinked to original sources

bioRxiv2023

Presenilin homologues influence substrate binding and processing by γ-secretase: a molecular simulation study.

Presenilin homologues in the {gamma}-secretase complex play a pivotal role in substrate binding and processing, impacting {beta}-amyloid (A{beta}) peptide generation in Alzheimers disease. We conducted a molecular simulation study to determine substrate preferences between presenilin-1 (PS1) and presenilin-2 (PS2) {gamma}-secretase enzymes for amyloid precursor protein (APP) and Notch1 processing. Using homology modelling, we generated PS1- and PS2-{gamma}-secretase models bound to substrates in the A{beta}40 and A{beta}42 generation pathways and Notch1 S3 and S4 cleavage site substrates. Metadynamics simulations and binding free energy calculations were used to explore conformational ensembles and substrate preferences. PS2-{gamma}-secretase exhibited increased conformational flexibility and preferential binding energy for initiating the A{beta}42 pathway compared to PS1-{gamma}-secretase. Additionally, Notch1 exhibits a preference for binding to PS2-{gamma}-secretase over PS1-{gamma}-secretase. This study provides valuable insights into the conformational dynamics of {gamma}-secretase bound to different substrates within a cleavage pathway, improving our understanding of substrate processivity. The findings highlight the importance of considering both PS1- and PS2-{gamma}-secretase in structure-based drug design efforts, with implications for stabilizing or destabilizing specific states during APP processing.

neuroscience↗

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

Statistical significance and biological relevance: The case of Nosema ceranae and winter colony losses.

Managed and wild insect pollinators play a key role in ensuring that mankind is adequately supplied with food. Among the pollinating insects, the managed Western honey bee providing about 90% of commercial pollination is of special importance. Hence, diseases as well as disease causing pathogens and parasites that threaten honey bees, have become the focus of many research studies. The ectoparasitic mite Varroa destructor together with deformed wing virus (DWV) vectored by the mite have been identified as the main contributors to colony losses, while the role of the microsporidium Nosema ceranae in colony losses is still controversially discussed. In an attempt to solve this controversy, we statistically analyzed a unique data set on honey bee colony health comprising data on mite infestation levels, Nosema spp. infections and winter losses continuously collected over 15 years. We used various statistical methods to investigate the relationship between colony mortality and the two pathogens, V. destructor and N. ceranae. Our multivariate statistical analysis confirmed that V. destructor is the major cause of colony winter losses. When using cumulative data sets, we also found a significant relationship between N. ceranae infections and colony losses. However, determining the effect size revealed that this statistical significance was of low biological relevance, because the deleterious effects of N. ceranae infection are normally masked by the more severe effects of V. destructor on colony health and therefore only detectable in the few colonies that are not infested with mites or are infested at low levels.

microbiology↗