Converging peripheral blood microRNA profiles in Parkinson's disease and progressive supranuclear palsy
Authors: Pavelka Lukas , Rauschenberger Armin , Hemedan Ahmed , Ostaszewski Marek , Glaab Enrico , Krüger Rejko ,   NCER-PD Consortium, Acharya Geeta , Aguayo Gloria , Alexandre Myriam , Ali Muhammad , Ammerlann Wim , Balling Rudi , Bassis Michele , Beaumont Katy , Becker Regina , Bellora Camille , Berchem Guy , Berg Daniela , Bisdorff Alexandre , Brockmann Kathrin , Calmes Jessica , Castillo Lorieza , Contesotto Gessica , Arena Giuseppe , Diederich Nico , Dondelinger Rene , Esteves Daniela , Fagherazzi Guy , Ferrand Jean-Yves , Gantenbein Manon , Gasser Thomas , Gawron Piotr , Ghosh Soumyabrata , Giraitis Marijus , Glaab Enrico , Gomes Clarissa , Gómez De Lope Elisa , Graas Jérôme , Graziano Mariella , Groues Valentin , Grünewald Anne , Gu Wei , Hammot Gaël , Hanff Anne-Marie , Hansen Linda , Hansen Maxime , Heneka Michael , Henry Estelle , Herbrink Sylvia , Herzinger Sascha , Heymann Michael , Hu Michele , Hundt Alexander , Paccoud Ivana , Jacoby Nadine , Jaroslaw Lebioda Jacek , Jaroz Yohan , Klopfenstein Quentin , Klucken Jochen , Krüger Rejko , Lambert Pauline , Landoulsi Zied , Lentz Roseline , Liepelt Inga , Liszka Robert , Longhino Laura , Lorentz Victoria , Cristina Lupu Paula , Mackay Clare , Maetzler Walter , Marcus Katrin , Marques Guilherme , Marques Tainá , Martins Conde Patricia , May Patrick , Mcintyre Deborah , Mediouni Chouaib , Meisch Francoise , Menster Myriam , Minelli Maura , Mittelbronn Michel , Mollenhauer Brit , Moreno Carlos , Mühlschlegel Friedrich , Nati Romain , Nehrbass Ulf , Nickels Sarah , Nicolai Beatrice , Nicolay Jean-Paul , Noor Fozia , Ostaszewski Marek , Paccontrolshek Sinthuja , Pauly Claire , Pauly Laure , Pavelka Lukas , Perquin Magali , Ramos Lima Rosalina , Rauschenberger Armin , Rawal Rajesh , Reddy Bobbili Dheeraj , Rosales Eduardo , Rosety Isabel , Rump Kirsten , Sandt Estelle , Sapienza Stefano , Satagopam Venkata , Schmitt Margaux , Schmitz Sabine , Schneider Reinhard , Schwamborn Jens , Schweitzer Jean-Edouard , Sharify Amir , Soboleva Ekaterina , Sokolowska Kate , Terwindt Olivier , Thien Hermann , Thiry Elodie , Ting Jiin Loo Rebecca , Trefois Christophe , Trouet Johanna , Tsurkalenko Olena , Vaillant Michel , Valenti Mesele , Van Schagen Sijmen , Vilas Boas Liliana , Vyas Maharshi , Wade-Martins Richard , Wilmes Paul , Wollscheid-Lengeling Evi , Zelimkhanov Gelani 
Published: May 2024

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.