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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.
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.
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1 Mayo Clinic, Department of Neuroscience, Jacksonville, USA (GRID:grid.417467.7) (ISNI:0000 0004 0443 9942); Mayo Clinic, Center for Clinical and Translational Science, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X); Mayo Clinic, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X)
2 Mayo Clinic, Department of Quantitative Health Sciences, Jacksonville, USA (GRID:grid.417467.7) (ISNI:0000 0004 0443 9942)
3 Mayo Clinic, Department of Neuroscience, Jacksonville, USA (GRID:grid.417467.7) (ISNI:0000 0004 0443 9942)
4 Mayo Clinic, Center for Clinical and Translational Science, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X)
5 University of Kentucky, Sanders-Brown Center on Aging, Lexington, USA (GRID:grid.266539.d) (ISNI:0000 0004 1936 8438); University of Kentucky, Department of Pathology & Laboratory Medicine, Lexington, USA (GRID:grid.266539.d) (ISNI:0000 0004 1936 8438)
6 University of Kentucky, Sanders-Brown Center on Aging, Lexington, USA (GRID:grid.266539.d) (ISNI:0000 0004 1936 8438); University of Kentucky, Department of Neuroscience, Lexington, USA (GRID:grid.266539.d) (ISNI:0000 0004 1936 8438)
7 Emory University, Department of Pharmacology and Chemical Biology, Department of Neurology, Emory Center for Neurodegenerative Disease, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502)
8 Mayo Clinic, Department of Neuroscience, Jacksonville, USA (GRID:grid.417467.7) (ISNI:0000 0004 0443 9942); Mayo Clinic, Department of Neurology, Jacksonville, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X)