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Abstract
This is the accompanying site for our manuscript at Nature Communications.
Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by cell-type-specific tau lesions in neurons and glia. Using bulk brain RNAseq, we identified PSP-associated genes and co-expression networks that are enriched with cell-type marker genes. We extended our work to identify cell-type-specific expression perturbations in PSP using a systems approach and in vivo validations in a model system.
Methods: Bulk-tissue and single-nucleus RNAseq were performed using frozen brain temporal cortex (TCX) samples from pathologically confirmed PSP and control participants. Differential expressed genes (DEG) between PSP and controls are identified. Modules of genes were constructed using weighted gene co-expression networks analysis (WGCNA). Top genes were identified and then validated using external bulk RNAseq datasets from a tau transgenic mouse model. Further, the ability of the validated DEGs to rescue tau-mediated cellular toxicity was evaluated in a tau transgenic Drosophila model.
Results: We observed massive expression perturbations in the brains of PSP patients that are concordant with prior publications. Moreover, we detected robust oligodendrocytic and astrocytic specific changes at bulk tissue and co-expression modules levels. Further snRNAseq analysis confirmed the cell-type-specific changes. Subsequently, we prioritized 240 DEGs with congruent cell-type-specific perturbations in snRNAseq and bulk RNAseq and validated those using transgenic mouse model data. Lastly, a significant number of the up-regulated glial genes, when knocked down in a tau transgenic Drosophila model, led to reduced tau-mediated cellular toxicity, suggesting novel potential therapeutic avenues. We augmented our findings by providing a list of existing drugs that can target the gene of interests.
Key Findings:
- PSP brains undergoes massive expression perturbations both at bulk and single-cell levels.
- Glial processes and pathways are impacted in PSP similar to that in other neurodegenerative diseases such as AD.
- Our drug discovery strategy highlighted DDR2 as a target for PSP with safe small molecule that can be reproposed from other clinical trials for PD/AD.
Are there any correlation between the WGCNA module and phenotypes?
We show the WGCNA module that the gene of interest is part of. For each module, we showed its correlation with various phenotypes, including:
- Correlation with PSP diagnosis : PSPvsCtrl
- Correlation with neuropathology tufted astrocytes : TA
- Correlation with neuropathology coiled body : CB
- Correlation with neuropathology neurofibrillary tangle : NFT
- Correlation with neuropathology tau threads : TauTh
- Correlation with overall neuropathology: Overall
Are there any enrichment of cell-specific genes in the modules?
We show the WGCNA modules that the gene of interest is part of. For each module, we showed its enrichment of the major cell type genes:
- Astrocyte
- Endothelia
- Microglia
- Neuron
- Oligodendrocyte
What are some enriched gene sets?
snRNAseq: expression of PSP vs control nuclei
Cell Type and Clusters
Clustering and cell type defination of the snRNAseq data.
Expression levels
Expression levels of the select genes in UMAP space, seperated by Diagnosis.
Validation from rTG4510 mouse model
The details and raw data from can be retrieved from AD Knowledge Portal . Here is the DEG summary statistics comparing trangenic mice expressing human 4R tau with control mice at 4.5 or 6 months.
GMR>hTau drosophila screening results
Eye image
Drug interations
Data retrieved from DGIdb , reporting the interaction of drugs and genes ( Freshour et al, 2021 ).
Acknowledgement
We would like to thank the patients and their families for their participation, without whom these studies would not have been possible. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal. The Mayo RNAseq study data was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price) using samples from The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, CurePSP Foundation, and support from Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, USA. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026, National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders); the NIA (P30 AG19610, Arizona Alzheimer’s Disease Core Center); the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center); the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001, to the Arizona Parkinson’s Disease Consortium); and the Michael J. Fox Foundation for Parkinson’s Research. Control brain samples from the University of Kentucky were from the UK-Alzheimer’s Disease Research Center (P30 AG072946). Additional support for these studies was provided by the NINDS grant R01-NS080820 (NET), NIA grant R01-AG061796 (NET), NIA grant U19-AG074879 (NET), Alzheimer’s Association Zenith Fellow Award (NET), and NCATS grant TL1 TR002380 (YM). We thank the Mayo Clinic Genome Analysis Core (GAC), Co-Directors, Julie M. Cunningham, PhD and Eric Wieben, PhD, and supervisor Julie Lau, for their collaboration in collection of omics data. We thank Drs. Jada Lewis, Karen Duff, David Westaway and David Borchelt for generating these lines of transgenic mice and providing us access to them. We thank Dr. Joshua Shulman, Dr. Tom Lee, and Yarong (Linda) Li from the Baylor College of Medicine for sharing additional Drosophila stocks and providing technical and intellectual contributions to the experiments. We thank Jason P. Sinnwell from Mayo Clinic Quantitative Health Sciences and Andrea P. Laack from Mayo Clinic IT for assisting with the deployment of our web application, PSP RNAseq Atlas. We thank Matthew A. Bockol from Mayo Clinic IT and Abby Linden from Sage Bionetworks for assisting with the deposition of the human RNAseq data.
AMP-AD
The data in this manuscript are available via the AD Knowledge Portal The AD Knowledge Portal is a platform for accessing data, analyses and tools generated by the Accelerating Medicines Partnership (AMP-AD) Target Discovery Program and other National Institute on Aging (NIA)-supported programs to enable open-science practices and accelerate translational learning. The data, analyses and tools are shared early in the research cycle without a publication embargo on secondary use. Data is available for general research use according to the following requirements for data access and data attribution. For access to content described in this manuscript see this link.
Funding
This project was supported by NIH funding R01-NS080820, U01-AG046139, R01-AG061796, U19-AG074879, and Alzheimer’s Association Zenith Fellow Award. Yuhao Min was supported by the Clinical and Translational Science Award (CTSA) Grant Number TL1-TR002380 from the National Center for Advancing Translational Science (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
How to cite
If you used any results from this website, please cite our manuscript.
Yuhao Min, Xue Wang, Özkan İş, Tulsi A. Patel, Gunli Gao, Joseph S. Reddy, Zachary S. Quicksall, Thuy Nguyen, Shu Lin, Frederick Q. Tutor-New, Jessica L. Chalk, Adriana O. Mitchell, Julia E. Crook, Peter Nelson, Linda Van Eldik, Minerva M. Carrasquillo, Dennis W. Dickson, Ke Zhang, Mariet Allen, Nilüfer Ertekin-Taner, Cross Species Systems Biology Discovers Glial DDR2, STOM, and KANK2 as Therapeutic Targets in Progressive Supranuclear Palsy, Nature Communications, 2023. https://doi.org/10.1038/s41467-023-42626-3
Contacts
For additional information, please contact the corresponding author of the manuscript: Nilüfer Ertekin-Taner, M.D., Ph.D. at taner.nilufer@mayo.edu
This website was developed by Yuhao Min at min.yuhao@mayo.edu. Please see the manuscript landing page for relevant code availability.
Visit our lab's website at: https://www.mayo.edu/research/labs/genetics-of-alzheimers-disease-and-endophenotypes/overview
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