Unraveling Targetable Systemic and Cell-Type-Specific Molecular Phenotypes of Alzheimer's and Parkinson's Brains With Digital Cytometry

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Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders worldwide, with age being their major risk factor. The increasing worldwide life expectancy, together with the scarcity of available treatment choices, makes it thus pressing to find the molecular basis of AD and PD so that the causing mechanisms can be targeted. To study these mechanisms, gene expression profiles have been compared between diseased and control brain tissues. However, this approach is limited by mRNA expression profiles derived for brain tissues highly reflecting their degeneration in cellular composition but not necessarily disease-related molecular states. We therefore propose to account for cell type composition when comparing transcriptomes of healthy and diseased brain samples, so that the loss of neurons can be decoupled from pathology-associated molecular effects. This approach allowed us to identify genes and pathways putatively altered systemically and in a cell-type-dependent manner in AD and PD brains. Moreover, using chemical perturbagen data, we computationally identified candidate small molecules for specifically targeting the profiled AD/PD-associated molecular alterations. Our approach therefore not only brings new insights into the disease-specific and common molecular etiologies of AD and PD but also, in these realms, foster the discovery of more specific targets for functional and therapeutic exploration.
This work was supported by European Molecular Biology Organization (EMBO Installation Grant 3057 to NB-M), Fundação para a Ciência e a Tecnologia (FCT Investigator Starting Grant IF/00595/2014 and CEEC Individual Assistant Researcher contract CEECIND/00436/2018 to NB-M, Ph.D.Studentship PD/BD/105854/2014 to MB), and Genome PT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 – Operational Programme for Competitiveness and Internationalization (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020),under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT).