Tau polarizes an aging transcriptional signature to excitatory neurons and glia
Abstract
Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell type-specific manner. Integration of cellular abundance and gene expression pinpoints Nuclear Factor Kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.
Data availability
All original single cell sequencing data have been uploaded to the Accelerating Medicines Parternship (AMP)-AD Knowledge Portal on Synapse and can be accessed through the DOI: https://doi.org/10.7303/syn35798807.1.
-
The Single-cell transcriptomic analysis of Alzheimer's disease (snRNAseqPFC_BA10) StudyAD Knowledge Portal: syn2580853.
-
A single-cell transcriptome atlas of the ageing Drosophila brainNCBI Gene Expression Omnibus, GSE107451.
-
Neuronal diversity and convergence in a visual system developmental atlasNCBI Gene Expression Omnibus, GSE142789.
Article and author information
Author details
Funding
National Institute on Aging (R01AG057339)
- Zhandong Liu
- Juan Botas
- Joshua M Shulman
Huffington Foundation
- Zhandong Liu
- Juan Botas
- Joshua M Shulman
McGee Family Foundation
- Joshua M Shulman
Duncan Neurological Research Institute
- Zhandong Liu
- Ismael Al-Ramahi
- Juan Botas
- Joshua M Shulman
Effie Marie Caine Endowed Chair for Alzheimer's Research
- Joshua M Shulman
National Institute on Aging (R01AG053960)
- Joshua M Shulman
National Institute on Aging (U01AG061357)
- Joshua M Shulman
National Institute on Aging (U01AG046161)
- Joshua M Shulman
Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555)
- Joshua M Shulman
National Institutes of Health (S10OD023469)
- Joshua M Shulman
National Institutes of Health (S10OD025240)
- Joshua M Shulman
Cancer Prevention and Research Institute of Texas (RP200504)
- Joshua M Shulman
Parkinson's Foundation (PF-PRF-830012)
- Hui Ye
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 193
- downloads
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Evolution of gene expression frequently drives antibiotic resistance in bacteria. We had previously (Patel and Matange, eLife, 2021) shown that, in Escherichia coli, mutations at the mgrB locus were beneficial under trimethoprim exposure and led to overexpression of dihydrofolate reductase (DHFR), encoded by the folA gene. Here, we show that DHFR levels are further enhanced by spontaneous duplication of a genomic segment encompassing folA and spanning hundreds of kilobases. This duplication was rare in wild-type E. coli. However, its frequency was elevated in a lon-knockout strain, altering the mutational landscape early during trimethoprim adaptation. We then exploit this system to investigate the relationship between trimethoprim pressure and folA copy number. During long-term evolution, folA duplications were frequently reversed. Reversal was slower under antibiotic pressure, first requiring the acquisition of point mutations in DHFR or its promoter. Unexpectedly, despite resistance-conferring point mutations, some populations under high trimethoprim pressure maintained folA duplication to compensate for low abundance DHFR mutants. We find that evolution of gene dosage depends on expression demand, which is generated by antibiotic and exacerbated by proteolysis of drug-resistant mutants of DHFR. We propose a novel role for proteostasis as a determinant of copy number evolution in antibiotic-resistant bacteria.
-
- Evolutionary Biology
- Genetics and Genomics
Expression quantitative trait loci (eQTLs) provide a key bridge between noncoding DNA sequence variants and organismal traits. The effects of eQTLs can differ among tissues, cell types, and cellular states, but these differences are obscured by gene expression measurements in bulk populations. We developed a one-pot approach to map eQTLs in Saccharomyces cerevisiae by single-cell RNA sequencing (scRNA-seq) and applied it to over 100,000 single cells from three crosses. We used scRNA-seq data to genotype each cell, measure gene expression, and classify the cells by cell-cycle stage. We mapped thousands of local and distant eQTLs and identified interactions between eQTL effects and cell-cycle stages. We took advantage of single-cell expression information to identify hundreds of genes with allele-specific effects on expression noise. We used cell-cycle stage classification to map 20 loci that influence cell-cycle progression. One of these loci influenced the expression of genes involved in the mating response. We showed that the effects of this locus arise from a common variant (W82R) in the gene GPA1, which encodes a signaling protein that negatively regulates the mating pathway. The 82R allele increases mating efficiency at the cost of slower cell-cycle progression and is associated with a higher rate of outcrossing in nature. Our results provide a more granular picture of the effects of genetic variants on gene expression and downstream traits.