Nature aging · 2025

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

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Saloner Rowan, Staffaroni Adam M, Dammer Eric B, Johnson Erik C B, Paolillo Emily W, Wise Amy, Heuer Hilary W, Forsberg Leah K, Lario-Lago Argentina, Webb Julia D, Vogel Jacob W, Santillo Alexander F, Hansson Oskar, Kramer Joel H, Miller Bruce L, Li Jingyao, Loureiro Joseph, Sivasankaran Rajeev, Worringer Kathleen A, Seyfried Nicholas T, Yokoyama Jennifer S, Spina Salvatore, Grinberg Lea T, Seeley William W, VandeVrede Lawren, Ljubenkov Peter A, Bayram Ece, Bozoki Andrea, Brushaber Danielle, Considine Ciaran M, Day Gregory S, Dickerson Bradford C, Domoto-Reilly Kimiko, Faber Kelley, Galasko Douglas R, Gendron Tania, Geschwind Daniel H, Ghoshal Nupur, Graff-Radford Neill, Hales Chadwick M, Honig Lawrence S, Hsiung Ging-Yuek R, Huey Edward D, Kornak John, Kremers Walter, Lapid Maria I, Lee Suzee E, Litvan Irene, McMillan Corey T, Mendez Mario F, Miyagawa Toji, Pantelyat Alexander, Pascual Belen, Masdeu Joseph, Paulson Henry L, Petrucelli Leonard, Pressman Peter, Rademakers Rosa, Ramos Eliana Marisa, Rascovsky Katya, Roberson Erik D, Savica Rodolfo, Snyder Allison, Sullivan Anna Campbell, Tartaglia M Carmela, Vandebergh Marijne, Boeve Brad F, Rosen Howie J, Rojas Julio C, Boxer Adam L, Casaletto Kaitlin B, ALLFTD Consortium

Аннотация

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of (1) sporadic progressive supranuclear palsy-Richardson syndrome and (2) frontotemporal dementia spectrum clinical syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

Предметные рубрики MeSH

Humans Frontotemporal Lobar Degeneration Male Proteomics Female Proteome Biomarkers Middle Aged tau Proteins Progranulins Aged C9orf72 Protein Adult Mutation

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

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Аннотация

Предметные рубрики MeSH