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

• Published in: Nature communications Vol. 14; no. 1; p. 6801
• Main Authors: Min, Yuhao, Wang, Xue, İş, Özkan, Patel, Tulsi A., Gao, Junli, Reddy, Joseph S., Quicksall, Zachary S., Nguyen, Thuy, Lin, Shu, Tutor-New, Frederick Q., Chalk, Jessica L., Mitchell, Adriana O., Crook, Julia E., Nelson, Peter T., Van Eldik, Linda J., Golde, Todd E., Carrasquillo, Minerva M., Dickson, Dennis W., Zhang, Ke, Allen, Mariet, Ertekin-Taner, Nilüfer
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-11-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/39; 38/89; 38/90; 38/91; 631/378/1689/364; 631/378/2583; 64; 64/24; 64/60; Animals; Basal ganglia; Biology; Brain; Central nervous system diseases; Data integration; Discoidin Domain Receptor 2; Disease; Gene expression; Genes; Health risk assessment; Humanities and Social Sciences; Humans; Insects; Mice; Movement disorders; multidisciplinary; Neurodegenerative diseases; Neuroglia - metabolism; Neurological diseases; Neuronal-glial interactions; Neuropathology; Neurosciences; Nominations; Paralysis; Pathology; Perturbation; Progressive supranuclear palsy; Proteins; Science; Science (multidisciplinary); Supranuclear Palsy, Progressive - pathology; Systems Biology; Tau protein; tau Proteins - metabolism; Tauopathies - pathology; Therapeutic applications; Therapeutic targets; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42626-3

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.
Progressive supranuclear palsy is a devastating neurological disorder without treatment. Here, the authors leveraged omics data and model organisms to nominate, prioritize, and validate high-confidence candidate genes as therapeutic targets.