Converging peripheral blood microRNA profiles in Parkinson's disease and progressive supranuclear palsy
Lukas Pavelka, Armin Rauschenberger, Ahmed Abdelmonem Hemedan, Marek Ostaszewski, Enrico Glaab, Rejko Krüger, Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Muhammad Ali, Wim Ammerlann, Rudi Balling, Michele Bassis, Katy Beaumont, Regina Becker, Camille Bellora, Guy Berchem, Daniela Berg, Alexandre Bisdorff, Kathrin Brockmann, Jessica Calmes, Lorieza Castillo, Gessica Contesotto, Giuseppe Arena, Nico J. Diederich, Rene Dondelinger, Daniela Esteves, Guy Fagherazzi, Jean-Yves Ferrand, Manon Gantenbein, Thomas Gasser, Piotr Gawron, Soumyabrata Ghosh, Marijus Giraitis, Enrico Glaab, Clarissa P. C. Gomes, Elisa Gómez de Lope, Jérôme Graas, Mariella Graziano, Valentin Grouès, Anne Grünewald, Wei Gu, Gaël Hammot, Anne-Marie Hanff, Linda Hansen, Maxime Hansen, Michael T. Heneka, Estelle Henry, Sylvia Herbrink, Sascha Herzinger, Michaël Heymann, Michele Hu, Alexander Hundt, Ivana Paccoud, Nadine Jacoby, Jacek Jaroslaw Lebioda, Yohan Jaroz, Quentin Klopfenstein, Jochen Klucken, Rejko Krüger, Pauline Lambert, Zied Landoulsi, Roseline Lentz, Inga Liepelt, Robert Liszka, Laura Longhino, Victoria Lorentz, Paula Cristina Lupu, Clare E. Mackay, Walter Maetzler, Katrin Marcus, Guilherme Fernandes Marques, Tainá M. Marques, Patricia Martins Conde, Patrick May, Deborah McIntyre, Chouaib Mediouni, Françoise Meisch, Myriam Menster, Maura Minelli, Michel Mittelbronn, Brit Mollenhauer, Carlos S. Moreno, Friedrich Mühlschlegel, Romain Nati, Ulf Nehrbass, Sarah Nickels, Béatrice Nicolaı̈, Jean-Paul Nicolay, Fozia Noor, Marek Ostaszewski, Sinthuja Paccontrolshek, Claire Pauly, Laure Pauly, Lukas Pavelka, Magali Perquin, Rosalina Ramos Lima, Armin Rauschenberger, Rajesh Rawal, Dheeraj Reddy Bobbili
Abstract
Abstract MicroRNAs act via targeted suppression of messenger RNA translation in the DNA–RNA–protein axis. The dysregulation of microRNA(s) reflects the epigenetic changes affecting the cellular processes in multiple disorders. To understand the complex effect of dysregulated microRNAs linked to neurodegeneration, we performed a cross-sectional microRNA expression analysis in idiopathic Parkinson's disease (n = 367), progressive supranuclear palsy (n = 35) and healthy controls (n = 416) from the Luxembourg Parkinson's Study, followed by prediction modelling, enriched pathway analysis and target simulation of dysregulated microRNAs using probabilistic Boolean modelling. Forty-six microRNAs were identified to be dysregulated in Parkinson's disease versus controls and 16 in progressive supranuclear palsy versus controls with 4 overlapping significantly dysregulated microRNAs between the comparisons. Predictive power of microRNA subsets (including up to 100 microRNAs) was modest for differentiating Parkinson's disease or progressive supranuclear palsy from controls (maximal cross-validated area under the receiver operating characteristic curve 0.76 and 0.86, respectively) and low for progressive supranuclear palsy versus Parkinson's disease (maximal cross-validated area under the receiver operating characteristic curve 0.63). The enriched pathway analysis revealed natural killer cell pathway to be dysregulated in both, Parkinson's disease and progressive supranuclear palsy versus controls, indicating that the immune system might play an important role in both diseases. Probabilistic Boolean modelling of pathway dynamics affected by dysregulated microRNAs in Parkinson's disease and progressive supranuclear palsy revealed partially overlapping dysregulation in activity of the transcription factor EB, endoplasmic reticulum stress signalling, calcium signalling pathway, dopaminergic transcription and peroxisome proliferator-activated receptor gamma coactivator-1α activity, though involving different mechanisms. These findings indicated a partially convergent (sub)cellular end-point dysfunction at multiple levels in Parkinson's disease and progressive supranuclear palsy, but with distinctive underlying molecular mechanisms.