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 Allen; Nilüfer Ertekin-Taner

doi:10.1038/s41467-023-42626-3

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 Allen

Nilüfer Ertekin-Taner

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 language	English
Article number	6801
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42626-3
State	Published - Dec 2023

Bibliographical note

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

Funding

We would like to thank the patients and their families for their participation, without whom these studies would not have been possible. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.org ). The Mayo RNAseq study data was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price) using samples from The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, CurePSP Foundation, and support from Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, USA. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026, National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders); the NIA (P30 AG19610, Arizona Alzheimer’s Disease Core Center); the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center); the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001, to the Arizona Parkinson’s Disease Consortium); and the Michael J. Fox Foundation for Parkinson’s Research. Control brain samples from the University of Kentucky were from the UK-Alzheimer’s Disease Research Center (P30 AG072946). Additional support for these studies was provided by the NINDS grant R01-NS080820 (NET), NIA grant R01-AG061796 (NET), NIA grant U19-AG074879 (NET), Alzheimer’s Association Zenith Fellows Award (NET), and NCATS grant TL1 TR002380 (YM). We thank the Mayo Clinic Genome Analysis Core (GAC), Co-Directors, Julie M. Cunningham, PhD and Eric Wieben, PhD, and supervisor Julie Lau, for their collaboration in collection of omics data. We thank Drs. Jada Lewis, Karen Duff, David Westaway and David Borchelt for generating these lines of transgenic mice and providing us access to them. We thank Dr. Joshua Shulman, Dr. Tom Lee, and Yarong (Linda) Li from the Baylor College of Medicine for sharing additional Drosophila stocks and providing technical and intellectual contributions to the experiments. We thank Jason P. Sinnwell from Mayo Clinic Quantitative Health Sciences and Andrea P. Laack from Mayo Clinic IT for assisting with the deployment of our web application, PSP RNAseq Atlas. We thank Matthew A. Bockol from Mayo Clinic IT and Abby Linden from Sage Bionetworks for assisting with the deposition of the human RNAseq data. We would like to thank the patients and their families for their participation, without whom these studies would not have been possible. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). The Mayo RNAseq study data was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price) using samples from The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, CurePSP Foundation, and support from Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, USA. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026, National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders); the NIA (P30 AG19610, Arizona Alzheimer’s Disease Core Center); the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center); the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001, to the Arizona Parkinson’s Disease Consortium); and the Michael J. Fox Foundation for Parkinson’s Research. Control brain samples from the University of Kentucky were from the UK-Alzheimer’s Disease Research Center (P30 AG072946). Additional support for these studies was provided by the NINDS grant R01-NS080820 (NET), NIA grant R01-AG061796 (NET), NIA grant U19-AG074879 (NET), Alzheimer’s Association Zenith Fellows Award (NET), and NCATS grant TL1 TR002380 (YM). We thank the Mayo Clinic Genome Analysis Core (GAC), Co-Directors, Julie M. Cunningham, PhD and Eric Wieben, PhD, and supervisor Julie Lau, for their collaboration in collection of omics data. We thank Drs. Jada Lewis, Karen Duff, David Westaway and David Borchelt for generating these lines of transgenic mice and providing us access to them. We thank Dr. Joshua Shulman, Dr. Tom Lee, and Yarong (Linda) Li from the Baylor College of Medicine for sharing additional Drosophila stocks and providing technical and intellectual contributions to the experiments. We thank Jason P. Sinnwell from Mayo Clinic Quantitative Health Sciences and Andrea P. Laack from Mayo Clinic IT for assisting with the deployment of our web application, PSP RNAseq Atlas. We thank Matthew A. Bockol from Mayo Clinic IT and Abby Linden from Sage Bionetworks for assisting with the deposition of the human RNAseq data.

Funders	Funder number
AD Knowledge Portal
CurePSP Foundation
National Institute on Aging	P50 AG016574, R01 AG017216, U01 AG006786, U01 AG006576, R01 AG025711, U01 AG046139, R01 AG018023, R01 AG003949, R01 AG032990
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	U24 NS072026, P30 AG19610
The Michael J Fox Foundation for Parkinson's Research
Mayo Clinic Rochester
Alzheimer's Association
National Center for Advancing Translational Sciences (NCATS)	TL1 TR002380
Mayo Foundation for Medical Education and Research
Arizona Department of Health Services	211002
Baylor College of Medicine
Arizona Biomedical Research Commission	4001, 0011, 1001, 05-901
Alzheimer's Disease Research Center, University of Pittsburgh	U19-AG074879, R01-AG061796, R01-NS080820

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

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

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10.1038/s41467-023-42626-3

Cite this

Min, Y., Wang, X., Iş, Ö., Patel, T. A., Gao, J., Reddy, J. S., Quicksall, Z. S., Nguyen, T., Lin, S., Tutor-New, F. Q., Chalk, J. L., Mitchell, A. O., Crook, J. E., Nelson, P. T., Van Eldik, L. J., Golde, T. E., Carrasquillo, M. M., Dickson, D. W., Zhang, K., ... Ertekin-Taner, N. (2023). Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy. Nature Communications, 14(1), Article 6801. https://doi.org/10.1038/s41467-023-42626-3

@article{de971edc515f40888ffea1a0768f8384,

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

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.",

author = "Yuhao Min and Xue Wang and {\"O}zkan I{\c s} and Patel, \{Tulsi A.\} and Junli Gao and Reddy, \{Joseph S.\} and Quicksall, \{Zachary S.\} and Thuy Nguyen and Shu Lin and Tutor-New, \{Frederick Q.\} and Chalk, \{Jessica L.\} and Mitchell, \{Adriana O.\} and Crook, \{Julia E.\} and Nelson, \{Peter T.\} and \{Van Eldik\}, \{Linda J.\} and Golde, \{Todd E.\} and Carrasquillo, \{Minerva M.\} and Dickson, \{Dennis W.\} and Ke Zhang and Mariet Allen and Nil{\"u}fer Ertekin-Taner",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-42626-3",

language = "English",

volume = "14",

number = "1",

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Min, Y, Wang, X, Iş, Ö, Patel, TA, Gao, J, Reddy, JS, Quicksall, ZS, Nguyen, T, Lin, S, Tutor-New, FQ, Chalk, JL, Mitchell, AO, Crook, JE, Nelson, PT , Van Eldik, LJ, Golde, TE, Carrasquillo, MM, Dickson, DW, Zhang, K, Allen, M & Ertekin-Taner, N 2023, 'Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy', Nature Communications, vol. 14, no. 1, 6801. https://doi.org/10.1038/s41467-023-42626-3

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

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 - https://www.scopus.com/pages/publications/85175709515#tab=citedBy

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DO - 10.1038/s41467-023-42626-3

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C2 - 37919278

AN - SCOPUS:85175709515

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VL - 14

JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

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