Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

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Fig. 1: Experimental design and characterization of TPR50 tau Tg mice in divergent genetic backgrounds.
Fig. 2: mRNA consensus coexpression network analysis.
Fig. 3: Transcriptomic and proteomic analyses in human FTD samples.
Fig. 4: miRNA coexpression network analysis.
Fig. 5: Overexpression of miR-203 in vitro and in vivo.
Fig. 6: Small-molecule inhibition of miR-203-induced cell death in vitro.

Data availability

miRNA-seq and mRNA-seq data from TPR50 tau mice, microarray data on PS19 hippocampus, microarray data on overexpression of miR-203 in vitro, RNA-seq on sorted mouse neurons and RNA-seq data with SAHA are available from the NCBI Gene Expression Omnibus database under Gene Expression Omnibus accession number GSE90696. Human FTD miRNA-seq and mRNA-seq data are available from https://www.synapse.org/#!Synapse:syn7818788. Human UPenn FTD Proteomics data are available from https://www.synapse.org/#!Synapse:syn9884357. The custom code used for the analysis can be accessed using this link in github: https://github.com/dhglab/Identification-of-evolutionarily-conserved-gene-networks-mediating-neurodegenerative-dementia

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Acknowledgements

Funding for this work was provided by Takeda Pharmaceuticals (D.H.G.), Rainwater Charitable Foundation/Tau consortium (D.H.G., S.J.H.), NIH grants to D.H.G., S.J.H., A.L. (5U01AG046161) and J.R. (5R25 NS065723) and Larry L. Hillblom Foundation Postdoctoral Fellowship to V.S. K.N., H.T., A.O., K.H. and S.K. are employees of Takeda Pharmaceuticals. The authors thank M. Hattori, Y. Obayashi and K. Nakamura for their contribution to the TPR50 mouse sample preparation and analysis. The authors thank M. Gearing at the Emory Alzheimer’s Disease Research Center brain bank for providing human FTD samples. The authors also thank N. Parikshak for help with network analysis and critical reading of the manuscript. We thank Eli Lilly and Company scientists for generating the Tg4510 microglia RNA-seq data and providing access to them. For the PSP and FTD temporal cortex RNA-seq dataset, study data were provided by the following sources: Mayo Clinic Alzheimer’s Disease Genetic Studies, led by N. Taner and S. G. Younkin, Mayo Clinic Jacksonville, using samples from the Mayo Clinic Study of Aging, Mayo Clinic Alzheimer’s Disease Research Center, and Mayo Clinic Brain Bank. Data collection was supported through funding by National Institute on Aging (NIA) grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. 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. Tg4510 replication and CRND8 RNA-seq data were provided by the NIH U01 AG046139. We thank J. Lewis, K. Duff, D. Westaway and D. Borchelt for generating these lines of transgenic mice and providing access to them.

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V.S. and D.H.G. planned and directed the experiments, guided the analysis and wrote the manuscript in conjunction with F.I.H. and J.E.R. All authors revised and edited the final version of the manuscript. F.I.H. performed all the experiments in mouse cortical cultures. V.S. performed all the bioinformatic analyses and performed dissections on human postmortem samples and isolated RNA. K.N., H.T., A.O., K.H. and S.K. bred the TPR50 mouse, characterized the F1 hybrids and collected the tissue samples. J.E.R. performed bioinformatic analysis using purified glial cells. J.E.R. and A.S. stained for and quantified inflammation in mouse brain samples. IFGC consortia members collected and analyzed FTD GWAS data. N.T.S., J.J.L. and A.I.L. performed mass spectrometry–based quantitative proteomics on human FTD samples obtained from M.G., V.M.V.D. and J.Q.T. The SAHA experiments were performed by C.C. and S.J.H. on human iPSC-derived neurons from tau and control patients.

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Correspondence to Daniel H. Geschwind.

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D.H.G. has received research funding from Takeda Pharmaceutical Company Limited. K.N., H.T., A.O., K.H. and S.K. are employees of Takeda Pharmaceutical Company Limited.

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Supplementary Table 1

TPR50 mRNA-seq Analysis

Supplementary Table 2

Human transcriptomics and proteomics data

Supplementary Table 3

TPR50 miRNA-seq analysis

Supplementary Table 4

Module preservation and connectivity map

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Swarup, V., Hinz, F.I., Rexach, J.E. et al. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. Nat Med 25, 152–164 (2019). https://doi.org/10.1038/s41591-018-0223-3

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