Systems Analysis Reveals Ageing-Related Perturbations in Retinoids and Sex Hormones in Alzheimer's and Parkinson's Diseases.

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

doi:10.3390/biomedicines9101310

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.

Highlights

Neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s diseases (PD), cause years of a healthy life to be lost
To reveal transcriptomic differences between Alzheimer’s disease (AD)/PD samples compared to healthy controls, we identified differentially expressed genes (DEGs) and performed gene set enrichment (GSE) analyses
In cluster 3, we found that DEGs were enriched in upregulated Gene Ontology (GO) terms associated with neuron function, olfaction, cell motility, and immune system

Summary

Introduction

Neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s diseases (PD), cause years of a healthy life to be lost. The current front-line therapies for AD and PD are cholinesterase inhibition and dopamine repletion, respectively, which are considered gold standards. These therapies are not capable of reversing neurodegeneration [1,2], necessitating potentially lifelong dependence on the drug and risking drug-associated complications. AD and PD are complex multifactorial diseases with heterogeneous underlying molecular mechanisms involved in their progression [3,4,5] This variability can explain the differences in patient response to other treatments such as oestrogen replacement therapy [6,7] and statin treatment [8,9].

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Results

Conclusion