Biology subjects

Jacobs, J. R.

Publications and source records attributed to Jacobs, J. R..

3 recordsLinked to original sources

bioRxiv2025

Dietary Interventions Modulate Cell Competition and Locomotor Decline in an Alzheimer's Disease Drosophila Model

Alzheimers Disease (AD) is a neurodegenerative disorder characterised by the accumulation of Amyloid-beta 42 (A{beta}42) plaques and cognitive decline. Using Drosophila models, we investigated the impact of diet on cell competition, a process that eliminates unfit cells and is involved in AD progression. Cell competition is present in AD flies, where unfit neurons express fweLoseB and azot, leading to their elimination and motor improvements. In this study, we fed AD and control (healthy) flies with either a yeast-based diet (YBD) or a synthetic diet (SAA) for up to 28 days and evaluated cell competition at the cellular level and locomotion as behavioural output. AD flies fed with YBD exhibited a peak of cell competition at day 14 of feeding, being cyclical over time and followed by a progressive locomotion decline. In contrast, the SAA diet delayed the activation of cell competition until day 21, coinciding with locomotion restoration. Moreover, the synthetic diet postponed A{beta} formation, suggesting a slower progression of AD. Overexpression of the human Flower (hFWE) isoforms in Drosophila photoreceptors revealed their conserved function in regulating cell competition, with hFWE1 identified as the sole loser isoform in neuronal context. Conversely, hFWE2, a winner isoform, induced higher levels of cell competition in a diet-dependent manner. hFWE3 and hFWE4 induced a milder effect on cell competition but also have a winner-like function. In YBD-fed AD flies, hFWE2 failed to promote efficient elimination of unfit cells over time, as these flies exhibited even worse locomotion decline than control flies without hFWE2. In contrast with SAA, expression of hFWE2 induced better locomotion outcomes. Our data seems to indicate that diet may regulate AD progression through cell competition regulation, highlighting the complex interplay between diet, cell competition, and AD progression and providing insights into potential therapeutic strategies.

cell biology↗

bioRxiv2024

Matrisome gene expression is altered during non-allometric heart growth in genetically enlarged Drosophila

The cardiac extracellular matrix (ECM) is critical to defining the biophysical properties of the heart that adapt to changing stresses with growth or disease. The ECM is commonly dysregulated in chronic disease such as hypertension, diabetes, and cardiomyopathies, often leading to the development of fibrosis. There are no treatment options to address most ECM cardiomyopathies, but developing therapeutic targets necessitates an understanding of the regulation of ECM remodelling. Here, we employ a larval Drosophila overgrowth model ("giant larvae") to overload the heart and alter ECM remodelling in vivo. These larvae grow to immense sizes without exhibiting hallmarks of obesity. Remarkably, cardiac ECM organization scales allometrically despite overload. The main effect observed is a change in Collagen fibril thickness, possibly reflecting changes to tension in the system. Overgrowth-induced changes in gene expression similarly suggest changes in Collagen assembly, such as a dramatic increase in LOXL2, the main Collagen crosslinking enzyme. This could indicate that larvae may compensate for the stress of overgrowth by stabilizing the Collagen network. The enlarged hearts of giant larvae cannot contract fully at systole. Taken together, this reveals non-allometric changes to cardiac form and output with increasing body size. Overall, our overgrowth model presents an intriguing opportunity to examine the ability of a system to tolerate overgrowth without the metabolic inputs of obesity.

molecular biology↗

bioRxiv2023

Cardiac function and ECM morphology are altered with high fat diets in Drosophila

Cardiovascular disease is characterized by aberrant and excessive extracellular matrix (ECM) remodelling, termed fibrosis. Fibrotic remodelling is typically triggered by inflammation, which occurs systemically in obesity. Despite the contribution of fibrosis to adverse clinical outcomes and disease progression, there are no available treatments for this condition. Developing therapeutics for chronic conditions requires an understanding of in vivo ECM regulation, and how the ECM responds to a systemic challenge. We have therefore developed a Drosophila model for obesity via chronic high fat diet feeding and evaluated the response of the cardiac ECM to this metabolic challenge. We found that this model displays a striking disorganization of the cardiac ECM, with corresponding deficits in heart function. Our study shows that different genotypes tolerate varying levels of high fat diets, and that some genotypes may require a different percentage of fat supplementation for achieving an optimal obesity phenotype.

molecular biology↗