Systems Analysis Reveals Ageing-Related Perturbations in Retinoids and Sex Hormones in Alzheimer’s and Parkinson’s Diseases
Simon Lam,
Nils Hartmann,
Rui Benfeitas,
Cheng Zhang,
Muhammad Arif,
Hasan Turkez,
Mathias Uhlén,
Christoph Englert,
Robert Knight,
Adil Mardinoglu
Affiliations
Simon Lam
Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
Nils Hartmann
Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany
Rui Benfeitas
National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, SE-17121 Stockholm, Sweden
Cheng Zhang
Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17121 Stockholm, Sweden
Muhammad Arif
Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17121 Stockholm, Sweden
Hasan Turkez
Department of Medical Biology, Faculty of Medicine, Atatürk University, 25240 Erzurum, Turkey
Mathias Uhlén
Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17121 Stockholm, Sweden
Christoph Englert
Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany
Robert Knight
Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
Adil Mardinoglu
Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
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.
