Journal Article

DZNE-2022-01328

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia.

Miedema, S. S. M. ; Mol, M. O. ; Koopmans, F. T. W. ; Hondius, D. C. ; van Nierop, P. ; Menden, K.DZNE* ; de Veij Mestdagh, C. F. ; van Rooij, J. ; Ganz, A. B. ; Paliukhovich, I. ; Melhem, S. ; Li, K. W. ; Holstege, H. ; Rizzu, P.DZNE* ; van Kesteren, R. E. ; van Swieten, J. C. ; Heutink, P.DZNE* ; Smit, A. B.

2022
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s40478-022-01387-8

Abstract: Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer's disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.

Keyword(s): Endothelial Cells: metabolism (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Humans (MeSH) ; Intercellular Signaling Peptides and Proteins: genetics (MeSH) ; Mutation: genetics (MeSH) ; Pick Disease of the Brain (MeSH) ; Progranulins: genetics (MeSH) ; Proteomics (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; Cell type enrichment ; Frontotemporal dementia ; GRN ; Human brain proteomics ; MAPT ; GRN protein, human ; Intercellular Signaling Peptides and Proteins ; MAPT protein, human ; Progranulins ; tau Proteins

Note: CC BY

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Contributing Institute(s):

1. Genome Biology of Neurodegenerative Diseases (AG Heutink 1)
2. Applied Genomics of Neurodegenerative Diseases (AG Rizzu)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2022

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