2025
article
Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes
Sogorb-Esteve A, Weiner S, Simrén J, Swift IJ, Bocchetta M, Todd Eg, Cash DM, Bouzigues A, Russell LL, Foster PH, Ferry-Bolder E, van Swieten Jc, Jiskoot LC, Seelaar H, Sánchez-Valle R, Laforce R, Graff C, Galimberti D, Vandenberghe R, de Mendonça A, Tiraboschi P, I. Santana, Gerhard Hambusch, Levin Myron J, Sorbi S, Otto M, Pasquier F, Ducharme S, Butler CR, Le Ber I, Finger Patricia E., Tartaglia MC, Masellis M, Rowe JB, Synofzik M, Moreno F, Borroni B, Genfi, Blennow K., Zetterberg H., Rohrer JD, Gobom J, David L. Thomas, Thomas Cope, Timothy Rittman, Alberto Benussi, Enrico Premi, Roberto Gasparotti, Archetti Silvana, Stefano Gazzina, Valentina Cantoni, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Radaaelli, David Tang-Wai, Ekaterina Rogaeva, Michel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara B. Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M. Papma, Lucia Giannini, Rick van Minkelen, Yolande A.L. Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Håkan Thonberg, Linn Öijerstedt, Vesna Jelić, Paul Thompson, Tobias Langheinrich, Albert Llado, Anna Antonell, Jaume Olives, Mircea Balasa, Núria Bargalló, Sergi Borrego‐Écija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Jorge Villanúa, Cañada Marta, Mikel Tainta, Miren Zulaica, Myriam Barandiarán, Patricial Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip van Damme, Rose Buffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Brice Alexis, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Virginia Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl‐Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso
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Résumé fourni par la source
We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.
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Sujets associés
Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative Diseases