Biology subjects

Palu, R.

Publications and source records attributed to Palu, R..

3 recordsLinked to original sources

bioRxiv2023

Prenatal alcohol exposure alters expression of genes involved in cell adhesion, immune response, and toxin metabolism in adolescent rat hippocampus

Prenatal alcohol exposure can result in mild to severe consequences for children throughout their lives, with this range of symptoms referred to as Fetal Alcohol Spectrum Disorders (FASD). These consequences are thought to be linked to changes in gene expression and transcriptional programming in the brain, but the identity of those changes, and how they persist into adolescence are unclear. In this study, we isolated RNA from the hippocampus of adolescent rats exposed to ethanol during prenatal development and compared gene expression to controls. Exposure to ethanol caused widespread downregulation of many genes as compared to control rats. Gene ontology analysis demonstrated that affected pathways included cell adhesion, toxin metabolism, and immune responses. Interestingly, these differences were not strongly affected by sex. Furthermore, these changes were consistent when comparing ethanol-exposed rats to pair-fed controls provided with a liquid diet and those fed ad libitum on a standard chow diet. We conclude from this study that changes in genetic architecture and the resulting neuronal connectivity after prenatal exposure to alcohol continue through adolescent development. Further research into the consequences of specific gene expression changes on neural and behavioral changes will be vital to our understanding of the FASD spectrum of diseases. AUTHOR SUMMARYAlcohol exposure during fetal development is associated with a wide range of behavioral and physical symptoms that can be observed from childhood throughout adolescence and beyond. It is believed that this exposure may alter gene expression patterns permanently by changing genomic architecture, but the actual changes themselves are still unclear. In this study we examined gene expression patterns in rats whose mothers were given ethanol during their pregnancies. These were compared to control rats whose mothers were fed a similar liquid diet without ethanol as well as rats fed a normal diet. We identified the top differentially expressed genes and performed gene ontology analysis to identify both genes and pathways important in the response to ethanol during fetal development. We focused on adolescent rats since prenatal alcohol exposure has been shown at this stage to influence behavior. We indeed found a number of significant changes in gene expression, suggesting that prenatal alcohol exposure has ongoing consequences throughout and likely beyond adolescence into adulthood. Pathways such as cell adhesion, immune response, and toxin response were all highlighted. Future work will focus on making connections between these gene expression changes and behavioral changes observed at this same life stage.

genetics↗

bioRxiv2021

A natural genetic variation screen identifies insulin signaling, neuronal communication, and innate immunity as modifiers of hyperglycemia in the absence of Sirt1

Variation in the onset, progression, and severity of symptoms associated with metabolic disorders such as diabetes impairs the diagnosis and treatment of at-risk patients. Diabetes symptoms, and patient variation in these symptoms, is attributed to a combination of genetic and environmental factors, but identifying the genes and pathways that modify diabetes in humans has proven difficult. A greater understanding of genetic modifiers and the ways in which they interact with metabolic pathways could improve the ability to predict a patients risk for severe symptoms, as well as enhance the development of individualized therapeutic approaches. In this study we use the Drosophila Genetic Reference Panel (DGRP) to identify genetic variation influencing hyperglycemia associated with loss of Sirt1 function. Through analysis of individual candidate functions, physical interaction networks, and Gene Set Enrichment Analysis (GSEA) we identify not only modifiers involved in canonical glucose metabolism and insulin signaling, but also genes important for neuronal signaling and the innate immune response. Furthermore, reducing the expression of several of these candidates suppressed hyperglycemia, making them ideal candidate therapeutic targets. These analyses showcase the diverse processes contributing to glucose homeostasis and open up several avenues of future investigation.

genetics↗

bioRxiv2018

Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response

Endoplasmic reticulum (ER) stress is an important modifier of human disease. Genetic variation in genes involved in the ER stress response has been linked to inter-individual differences in this response. However, the mechanisms and pathways by which genetic modifiers are acting on the ER stress response remain unclear. In this study, we characterize the role of the long chain fatty acid elongase Baldspot (ELOVL6) in modifying the ER stress response and disease. We demonstrate that loss of Baldspot rescues degeneration and reduces IRE1 and PERK signaling and cell death in a Drosophila model of retinitis pigmentosa and ER stress (Rh1G69D). Dietary supplementation of stearate bypasses the need for Baldspot activity. Finally, we demonstrate that Baldspot regulates the ER stress response across different tissues and induction methods. Our findings suggest that ELOVL6 is a promising target in the treatment of not only retinitis pigmentosa, but a number of different ER stress-related disorders.\n\nAUTHOR SUMMARYDifferences in genetic background drives disease variability, even among individuals with identical, causative mutations. Identifying and understanding how genetic variation impacts disease expression could improve diagnosis and treatment of patients. Previous work has linked the endoplasmic reticulum (ER) stress response pathway to disease variability. When misfolded proteins accumulate in the ER, the ER stress response returns the cell to its normal state. Chronic ER stress leads to massive amounts of cell death and tissue degeneration. Limiting tissue loss by regulating the ER stress response has been a major focus of therapeutic development. In this study, we characterize a novel regulator of the ER stress response, the long chain fatty acid elongase Baldspot/ELOVL6. In the absence of this enzyme, cells undergoing ER stress display reduced cell death, and degeneration in a Drosophila disease model. Feeding of excess fatty acids increases degeneration to original disease levels, linking the regulatory activity of Baldspot to its enzymatic activity. Finally, we demonstrate that Baldspot can alter the ER stress response under a variety of other ER stress conditions. Our studies demonstrate that Baldspot/ELOVL6 is a ubiquitous regulator of the ER stress response and is a good candidate therapeutic target.

genetics↗