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

Autor: Min Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, USA.; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA., Wang X; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., İş Ö; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Patel TA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Gao J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Reddy JS; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Quicksall ZS; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Nguyen T; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Lin S; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Tutor-New FQ; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Chalk JL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Mitchell AO; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Crook JE; Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, USA., Nelson PT; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.; Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington, KY, USA., Van Eldik LJ; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.; Department of Neuroscience, University of Kentucky, Lexington, KY, USA., Golde TE; Department of Pharmacology and Chemical Biology, Department of Neurology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA., Carrasquillo MM; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Zhang K; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Allen M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Ertekin-Taner N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. taner.nilufer@mayo.edu.; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. taner.nilufer@mayo.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Nov 02; Vol. 14 (1), pp. 6801. Date of Electronic Publication: 2023 Nov 02.
DOI: 10.1038/s41467-023-42626-3
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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