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Systems analysis reveals ageing-related perturbations in retinoids and sex hormones in alzheimer’s and parkinson’s diseases

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Simon Lam, Nils Hartmann, Rui Benfeitas, Cheng Zhang, Muhammad Arif, Hasan Turkez, Mathias Uhlén, Christoph Englert, Robert Knight, Adil Mardinoglu

Original languageEnglish
Article number1310
JournalBiomedicines
Volume9
Issue number10
Early online date24 Sep 2021
DOIs
E-pub ahead of print24 Sep 2021
PublishedOct 2021

Bibliographical note

Funding Information: Funding: This work was supported by the German Ministry for Education and Research within the framework of the GerontoSys initiative (research core JenAge, funding code BMBF 0315581) to C.E.; and the Knut and Alice Wallenberg Foundation (grant number 2017.0303) to A.M. Funding Information: Acknowledgments: We are grateful to Catarina Henriques and Miguel Godinho Ferreira for sharing the tert mutant zebrafish line. We also thank Ivonne Heinze, Ivonne Görlich, and Marco Groth from the FLI sequencing facility for sequencing the zebrafish samples. The authors acknowledge use of the research computing facility at King’s College London, Rosalind (https://rosalind.kcl.ac.uk; accessed on 17 July 2019). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 6 December 2019. The results published here are in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.synapse.org; accessed on 1 October 2020). Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNAseq), R01AG48015 (monocyte RNAseq), RF1AG57473 (single nucleus RNAseq), U01AG32984 (genomic and whole exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161(TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc. rush.edu; accessed on 1 October 2020). We thank the patients and their families for their selfless donation to further understanding Alzheimer’s disease. This project was supported by funding from the National Institute on Aging (AG034504 and AG041232). Many data and biomaterials were collected from several National Institute on Aging (NIA) and National Alzheimer’s Coordinating Center (NACC, grant #U01 AG016976) funded sites. Amanda J. Myers, PhD (University of Miami, Department of Psychiatry), prepared the series. The directors, pathologist and technicians involved include Rush University Medical Center; Rush Alzheimer’s Disease Center (NIH #AG10161); David A. Bennett, M.D.; Julie A. Schneider, MD, MS; Karen Skish, MS, PA (ASCP) MT; Wayne T Longman. The Rush portion of this study was supported by National Institutes of Health grants P30AG10161, R01AG15819, R01AG17917, R01AG36042, R01AG36836, U01AG46152, R01AG34374, R01NS78009, U18NS82140, R01AG42210, and R01AG39478, and the Illinois Department of Public Health. Quality control checks and preparation of the gene expression data was provided by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s diseases (PD), are complex heterogeneous diseases with highly variable patient responses to treatment. Due to the growing evidence for ageing-related clinical and pathological commonalities between AD and PD, these diseases have recently been studied in tandem. In this study, we analysed transcriptomic data from AD and PD patients, and stratified these patients into three subclasses with distinct gene expression and metabolic profiles. Through integrating transcriptomic data with a genome-scale metabolic model and validating our findings by network exploration and co-analysis using a zebrafish ageing model, we identified retinoids as a key ageing-related feature in all subclasses of AD and PD. We also demonstrated that the dysregulation of androgen metabolism by three different independent mechanisms is a source of heterogeneity in AD and PD. Taken together, our work highlights the need for stratification of AD/PD patients and development of personalised and precision medicine approaches based on the detailed characterisation of these subclasses.

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