Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy

Yuhao Min, Xue Wang, Özkan Iş, Tulsi A. Patel, Junli 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 T. Nelson, Linda J. Van Eldik, Todd E. Golde, Minerva M. Carrasquillo, Dennis W. Dickson, Ke Zhang, Mariet AllenNilüfer Ertekin-Taner

Research output: Contribution to journalArticlepeer-review

Abstract

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue (n = 408) and single nucleus RNAseq (n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM, and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas (https://rtools.mayo.edu/PSP_RNAseq_Atlas/). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.

Original languageEnglish
Article number6801
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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