Biology subjects

Sedivy, J.

Publications and source records attributed to Sedivy, J..

4 recordsLinked to original sources

bioRxiv2026

Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease

Cellular senescence contributes to neurodegeneration in Alzheimers disease (AD), yet brain-penetrant senotherapeutic strategies remain limited. Here, we identify long interspersed nuclear element 1 (LINE-1) retrotransposons as key regulators of neuronal senescence and the senescence-associated-secretory-phenotype (SASP) in AD. Using transdifferentiated induced neurons (iNs) that preserve donor-specific aging-associated molecular signatures, we show that pharmacological inhibition of LINE-1 with nucleoside reverse transcriptase inhibitors (nRTIs) or antisense oligonucleotides reduces p16 expression, suppresses SASP and interferon-stimulated gene programs, and attenuates paracrine induction of reactive astrogliosis. Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain. Although bulk analysis finds no significant differences in LINE-1 expression between AD and control neurons, long-read single-cell RNA sequencing of iNs identifies a subset of neurons with elevated LINE-1 activity which display transcriptional signatures of neurodegeneration, immune activation, and senescence are enriched in AD relative to controls. RNA velocity analysis indicates that LINE-1 activation precedes the induction of canonical senescence markers, supporting a causal rather than consequential role. Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression. Together, these findings establish a LINE-1/cGAS-STING axis as a driver of neuronal senescence in AD and highlight LINE-1 inhibition as a tractable senomorphic strategy for neurodegenerative disease.

neuroscience↗

bioRxiv2024

cGAS deficient mice display premature aging associated with de-repression of LINE1 elements and inflammation

Aging-associated inflammation, or inflammaging" is a driver of multiple age-associated diseases. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that functions to activate interferon response upon detecting viral DNA in the cytoplasm. cGAS contributes to inflammaging by responding to endogenous signals such as damaged DNA or LINE1 (L1) cDNA which forms in aged cells. While cGAS knockout mice are viable their aging has not been examined. Unexpectedly, we found that cGAS knockout mice exhibit accelerated aging phenotype associated with induction of inflammation. Transcription of L1 elements was increased in both cGAS knockout mice and in cGAS siRNA knockdown cells associated with high levels of cytoplasmic L1 DNA and expression of ORF1 protein. Cells from cGAS knockout mice showed increased chromatin accessibility and decreased DNA methylation on L1 transposons. Stimulated emission depletion microscopy (STED) showed that cGAS forms nuclear condensates that co-localize with H3K9me3 heterochromatin marks, and H3K9me3 pattern is disrupted in cGAS knockout cells. Taken together these results suggest a previously undescribed role for cGAS in maintaining heterochromatin on transposable elements. We propose that loss of cGAS leads to loss of chromatin organization, de-repression of transposable elements and induction of inflammation resulting in accelerated aging.

cell biology↗

bioRxiv2021

Myofibroblast Senescence Promotes Arrhythmogenic Remodeling in the Aged Infarcted Rabbit Heart

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in large animals, and the mechanisms are unknown. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a twelve-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast- cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that senolytic drugs may mitigate arrhythmias post-MI.

cell biology↗

bioRxiv2021

LINE-1 Retrotransposon expression in cancerous, epithelial and neuronal cells revealed by 5'-single cell RNA-Seq

LINE-1 retrotransposons are sequences capable of copying themselves to new genomic loci via an RNA intermediate. New studies implicate LINE-1 in a range of diseases, especially in the context of aging, but without an accurate understanding of where and when LINE-1 is expressed, a full accounting of its role in health and disease is not possible. We therefore developed a method - 5 scL1seq - that makes use of a widely available library preparation method (10x Genomics 5 single cell RNA-seq) to measure LINE-1 expression in tens of thousands of single cells. We recapitulated the known pattern of LINE-1 expression in tumors - present in cancer cells, absent from immune cells - and identified hitherto undescribed LINE-1 expression in human epithelial cells and mouse hippocampal neurons. In both cases, we saw a modest increase with age, supporting recent research connecting LINE-1 to age related diseases.

bioinformatics↗