TY - JOUR
T1 - Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy
AU - Min, Yuhao
AU - Wang, Xue
AU - Iş, Özkan
AU - Patel, Tulsi A.
AU - Gao, Junli
AU - Reddy, Joseph S.
AU - Quicksall, Zachary S.
AU - Nguyen, Thuy
AU - Lin, Shu
AU - Tutor-New, Frederick Q.
AU - Chalk, Jessica L.
AU - Mitchell, Adriana O.
AU - Crook, Julia E.
AU - Nelson, Peter T.
AU - Van Eldik, Linda J.
AU - Golde, Todd E.
AU - Carrasquillo, Minerva M.
AU - Dickson, Dennis W.
AU - Zhang, Ke
AU - Allen, Mariet
AU - Ertekin-Taner, Nilüfer
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85175709515&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-42626-3
DO - 10.1038/s41467-023-42626-3
M3 - Article
C2 - 37919278
AN - SCOPUS:85175709515
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6801
ER -
