Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration-Reference-Cited by-同舟云学术

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

Published:2024-03-28 Issue: Volume: Page:
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Author:

Saloner Rowan¹^ORCID,Staffaroni Adam¹^ORCID,Dammer Eric²^ORCID,Johnson Erik C.B.³^ORCID,Paolillo Emily¹,Wise Amy¹,Heuer Hilary¹,Forsberg Leah⁴,Lago Argentina Lario¹,Webb Julia¹,Vogel Jacob⁵,Santillo Alexander⁵,Hansson Oskar⁵^ORCID,Kramer Joel¹,Miller Bruce⁶,Li Jingyao⁷,Loureiro Joseph,Sivasankaran Rajeev⁸^ORCID,Worringer Kathleen⁹,Seyfried Nicholas³^ORCID,Yokoyama Jennifer¹⁰^ORCID,Seeley William¹¹,Spina Salvatore¹^ORCID,Grinberg Lea¹¹^ORCID,VandeVrede Lawren¹^ORCID,Ljubenkov Peter¹,Bayram Ece¹²,Bozoki Andrea¹³,Brushaber Danielle⁴^ORCID,Considine Ciaran¹⁴,Day Gregory¹⁵^ORCID,Dickerson Bradford¹⁶^ORCID,Domoto-Reilly Kimiko¹⁷^ORCID,Faber Kelley¹⁸,Galasko Douglas¹⁹^ORCID,Geschwind Daniel²⁰^ORCID,Ghoshal Nupur²¹^ORCID,Graff-Radford Neill⁴,Hales Chadwick²,Honig Lawrence²²^ORCID,Hsiung Ging-Yuek²³^ORCID,Huey Edward²²,Kornak John¹,Kremers Walter⁴,Lapid Maria⁴^ORCID,Lee Suzee¹,Litvan Irene²⁴^ORCID,McMillan Corey²⁵,Mendez Mario^ORCID,Miyagawa Toji⁴,Pantelyat Alexander²⁶,Pascual Belen²⁷^ORCID,Paulson Henry²⁸,Petrucelli Leonard⁴,Pressman Peter²⁹,Ramos Eliana³⁰,Rascovsky Katya¹,Roberson Erik³¹^ORCID,Savica Rodolfo⁴,Snyder Allison³²^ORCID,Sullivan A. Campbell³³,Tartaglia Carmela³⁴^ORCID,Vandebergh Marijne³⁵^ORCID,Boeve Bradley⁴^ORCID,Rosen Howie¹,Rojas Julio¹,Boxer Adam³⁶,Casaletto Kaitlin¹

Affiliation:

1. University of California, San Francisco

2. Emory University

3. Emory University School of Medicine

4. Mayo Clinic

5. Lund University

6. University of California San Francisco

7. Novartis Institutes for Biomedical Research, Inc.

8. Novartis Institutes for Biomedical Research

9. Novartis (United States)

10. UCSF

11. University of California at San Francisco

12. University of California, San Diego

13. University of North Carolina

14. Vanderbilt University

15. Mayo Clinic in Florida

16. Harvard University

17. University of Washington

18. Indiana University

19. UC San Diego

20. UCLA Health System and David Geffen School of Medicine

21. Washington University

22. Columbia University

23. University of British Columbia

24. UCSD

25. Department of Neurology, University of Pennsylvania, Philadelphia, USA

26. Johns Hopkins University

27. Houston Methodist

28. University of Michigan–Ann Arbor

29. University of Colorado

30. University of California, Los Angeles

31. University of Alabama at Birmingham

32. National Institutes of Health

33. University of Texas Health San Antonio

34. University of Toronto

35. University of Antwerp

36. Memory and Aging Center, Department of Neurology, University of California, San Francisco

Abstract

Abstract 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.

Publisher

Research Square Platform LLC

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