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

Saloner R, Staffaroni AM, Dammer EB, Johnson ECB, Paolillo EW, Wise A, Heuer HW, Forsberg LK, Lario-Lago A, Webb JD, Vogel JW, Santillo AF, Hansson O, Kramer JH, Miller BL, Li J, Loureiro J, Sivasankaran R, Worringer KA, Seyfried NT, Yokoyama JS, Spina S, Grinberg LT, Seeley WW, VandeVrede L, Ljubenkov PA, Bayram E, Bozoki A, Brushaber D, Considine CM, Day GS, Dickerson BC, Domoto-Reilly K, Faber K, Galasko DR, Gendron T, Geschwind DH, Ghoshal N, Graff-Radford N, Hales CM, Honig LS, Hsiung GR, Huey ED, Kornak J, Kremers W, Lapid MI, Lee SE, Litvan I, McMillan CT, Mendez MF, Miyagawa T, Pantelyat A, Pascual B, Masdeu J, Paulson HL, Petrucelli L, Pressman P, Rademakers R, Ramos EM, Rascovsky K, Roberson ED, Savica R, Snyder A, Sullivan AC, Tartaglia MC, Vandebergh M, Boeve BF, Rosen HJ, Rojas JC, Boxer AL, Casaletto KB, ALLFTD Consortium

Nat Aging 5 (6) 1143-1158 [2025-06-00; online 2025-05-16]

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.

PubMed 40380000

DOI 10.1038/s43587-025-00878-2

Crossref 10.1038/s43587-025-00878-2

pmc: PMC12234358
pii: 10.1038/s43587-025-00878-2