Biology subjects

Lindner, J.

Publications and source records attributed to Lindner, J..

5 recordsLinked to original sources

bioRxiv2025

Social isolation of aged mice drives dramatic release of inflammatory lipoxygenase-derived oxylipins

Oxylipins, signalling molecules derived from polyunsaturated fatty acids, act as key mediators controlling inflammatory processes. Ageing fuels the disruption of this network, promoting inflammageing. Social isolation, a common feature of ageing, may contribute to the emergence of pro-inflammatory responses, further aggravating conditions like cognitive decline and frailty. Here, we studied how repeated social isolation impacts inflammation-related oxylipin profiles in seven different organs and serum of aged mice. Additionally, we explored physical exercise as a tool to ameliorate age- and isolation-associated inflammation. Our results show that social isolation induces significant increases in interleukin-1{beta} levels and stimulates a dramatic production of lipoxygenase (LOX)-derived oxylipins in an organ-dependent manner, particularly pronounced in liver, lung, and spleen. Physical exercise failed to mitigate the pro-inflammatory effects induced by social isolation. These effects did not occur in the circulatory system as serum oxylipin levels remained relatively unchanged by isolation. The unexpected and striking elevation of oxylipins across the organs highlights the detrimental effect of social isolation and proposes key roles of oxylipins in stress-related inflammageing.

immunology↗

bioRxiv2024

Functional gene embeddings improve rare variant polygenic risk scores

Rare variant association testing is a powerful strategy for identifying effector genes underlying common traits. However, its effectiveness is limited by the scarcity of high-impact rare allele carriers, posing challenges for sensitivity and robustness. Here, we introduce FuncRVP, a rare variant association framework addressing this issue by leveraging functional information across genes. FuncRVP models the effects of rare variants as a weighted sum of gene impairment scores, with weights regularized through a prior based on functional gene embeddings. Modeling 41 quantitative traits from unrelated UK Biobank participants showed that FuncRVP consistently outperformed linear regressions on significantly associated genes and did so more effectively for traits with higher burden heritability. The framework demonstrated versatility, yielding consistent improvements across diverse gene embeddings. Moreover, FuncRVP generated more robust gene effect estimates and yielded more gene discoveries, especially among genetically constrained genes. These findings demonstrate the value of integrating functional information in rare variant association studies and showcase FuncRVP as a promising tool for enhancing phenotype prediction and gene discovery.

genetics↗

bioRxiv2023

Aberrant expression prediction across human tissues

Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compiled an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 49 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE showed mild predictive ability (1-1.6% average precision). Leveraging these and further variant annotations, we next trained AbExp, a model that yielded 12% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues led to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions.

genetics↗

bioRxiv2020

Novel proteostasis reporter mouse reveals different effects of cytoplasmic and nuclear aggregates on protein quality control in neurons

The cellular protein quality control machinery is important for preventing protein misfolding and aggregation, and decline in protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how proteostasis capacity of neurons changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc), a conformationally unstable protein that requires chaperones for proper folding and sensitively reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked impairment in proteostasis in tauopathy mice, but not in Huntingtons disease mice. Mechanistic investigations in primary neuronal cultures demonstrate that cytoplasmic, but not nuclear, aggregates cause defects of cellular protein quality control. Thus, the Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

neuroscience↗

bioRxiv2018

Peripheral blood exosomes pass blood-brain-barrier and induce glial cell activation

BackgroundExosomes are involved in intracellular communication and contain proteins, mRNAs, miRNAs, and signaling molecules. Exosomes were shown to act as neuroinflammatory mediators involved in neurodegenerative diseases including Alzheimers disease (AD), Parkinsons disease (PD), amyotrophic lateral sclerosis (ALS). Brain aging has been associated to increased neuroinflammation. In addition, a decreased extracellular vesicle concentration was observed in aging tissues. The specific mechanisms how exosomes and aging are connected are not known yet.\n\nResultsHere we have shown that peripheral injection had almost no effect on selected gene expression in the liver. However, exosome injection has led to changes in the specific markers of glial cell activation (CD68, Iba1, GFAP). Interestingly, only injection of exosomes isolated from aged mice induced significant activation of astrocyte cells, as shown by increased GFAP expression.\n\nConclusionTranscription levels of genes GFAP, TGF-{beta}, CD68, Iba1 known to be involved in glial cell function are significantly changing after introduction of peripheral extracellular vesicles. Exosomes were able to pass blood brain barrier and induce glial cell activation. GFAP known to be a specific astrocyte activation marker was significantly higher expressed after injection of old but not young exosomes, indicating a possible role of exosomes in the mechanisms of brain aging.

neuroscience↗