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DOI 10.21203/rs.3.rs-4103685/v1

Медицинская библиотека · Research square · 2024

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

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

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Аннотация

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. 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, MAPT) compared to 39 noncarrier 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 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.

Для цитирования: Saloner Rowan, Staffaroni Adam, Dammer Eric, Johnson Erik C B, Paolillo Emily, Wise Amy, Heuer Hilary, Forsberg Leah, Lago Argentina Lario, Webb Julia, Vogel Jacob, Santillo Alexander, Hansson Oskar, Kramer Joel, Miller Bruce, Li Jingyao, Loureiro Joseph, Sivasankaran Rajeev, Worringer Kathleen, Seyfried Nicholas, Yokoyama Jennifer, Seeley William, Spina Salvatore, Grinberg Lea, VandeVrede Lawren, Ljubenkov Peter, Bayram Ece, Bozoki Andrea, Brushaber Danielle, Considine Ciaran, Day Gregory, Dickerson Bradford, Domoto-Reilly Kimiko, Faber Kelley, Galasko Douglas, Geschwind Daniel, Ghoshal Nupur, Graff-Radford Neill, Hales Chadwick, Honig Lawrence, Hsiung Ging-Yuek, Huey Edward, Kornak John, Kremers Walter, Lapid Maria, Lee Suzee, Litvan Irene, McMillan Corey, Mendez Mario, Miyagawa Toji, Pantelyat Alexander, Pascual Belen, Paulson Henry, Petrucelli Leonard, Pressman Peter, Ramos Eliana, Rascovsky Katya, Roberson Erik, Savica Rodolfo, Snyder Allison, Sullivan A Campbell, Tartaglia Carmela, Vandebergh Marijne, Boeve Bradley, Rosen Howie, Rojas Julio, Boxer Adam, Casaletto Kaitlin. Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.. Research square. 2024. DOI: 10.21203/rs.3.rs-4103685/v1.
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