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Series GSE263929 Query DataSets for GSE263929
Status Public on May 24, 2024
Title Senescent glia link neuronal mitochondrial dysfunction and lipid droplet accumulation with age [19082_28_MASTER]
Organism Drosophila melanogaster
Experiment type Expression profiling by high throughput sequencing
Summary Senescence is a cellular state linked to aging and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumor formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. While senescent cells are active targets for anti-aging therapy, why these cells form in vivo, how they affect tissue aging, and the impact of their elimination remain unclear. Here we identify naturally-occurring senescent glia in aged Drosophila brains and decipher their origin and influence. Using AP1 activity to screen for senescence, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly life and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally-occurring senescent glia in vivo and indicate that these cells link key aging phenomena: mitochondrial dysfunction and lipid accumulation.
 
Overall design Through bulk-RNA-seq and a targeted RNAi screen, we determined that loss of select mitochondrial genes in neurons can trigger AP1 activity in glia. To determine if neuronal RNAi-induced AP1+ glia have features of senescence, we FACS-sorted and bulk-RNA-sequenced dsRed+ and dsRedneg cells from brains of 10d old flies with neuronal loss of inner complex genes. For this, an inducible pan-neuronal driver (elav-GeneSwitch) was used to express UAS-RNAi (UAS-ND42-RNAi or UAS-NP15.6-RNAi); cells with AP1 activity were identified using a genomic fluorescent reporter under the control of an AP1 binding motif (dsRed). Whole brains were dissected from 10d flies, dissociated into a cell suspension then dsRed+ and dsRedneg cells were FACS-isolated and bulk RNA-sequenced for downstream gene expression analysis (n=500 cells per biological replicate, 4 replicates).
 
Contributor(s) Byrns CN, Perlegos AE, Bonini NM
Citation(s) 38839958
Submission date Apr 14, 2024
Last update date Jun 14, 2024
Contact name Nancy M Bonini
E-mail(s) nbonini@sas.upenn.edu
Organization name University of Pennsylvania
Department Biology
Street address 433 S University Ave
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
 
Platforms (1)
GPL25244 Illumina NovaSeq 6000 (Drosophila melanogaster)
Samples (16)
GSM8207571 dsRed+_ND42RNAi_10d_rep1
GSM8207572 dsRed+_ND42RNAi_10d_rep2
GSM8207573 dsRed+_ND42RNAi_10d_rep3
Relations
BioProject PRJNA1100202

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Supplementary file Size Download File type/resource
GSE263929_RAW.tar 1.0 Mb (http)(custom) TAR (of TSV)
SRA Run SelectorHelp
Raw data are available in SRA

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