Home > Publications Database > Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia. > print

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037 _ _ |a DZNE-2022-01328
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082 _ _ |a 610
100 1 _ |a Miedema, Suzanne S M
|b 0
245 _ _ |a Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia.
260 _ _ |a London
|c 2022
|b Biomed Central
336 7 _ |a article
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520 _ _ |a 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.
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650 _ 7 |a Cell type enrichment
|2 Other
650 _ 7 |a Frontotemporal dementia
|2 Other
650 _ 7 |a GRN
|2 Other
650 _ 7 |a Human brain proteomics
|2 Other
650 _ 7 |a MAPT
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650 _ 7 |a GRN protein, human
|2 NLM Chemicals
650 _ 7 |a Intercellular Signaling Peptides and Proteins
|2 NLM Chemicals
650 _ 7 |a MAPT protein, human
|2 NLM Chemicals
650 _ 7 |a Progranulins
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 2 |a Endothelial Cells: metabolism
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: genetics
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: pathology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Intercellular Signaling Peptides and Proteins: genetics
|2 MeSH
650 _ 2 |a Mutation: genetics
|2 MeSH
650 _ 2 |a Pick Disease of the Brain
|2 MeSH
650 _ 2 |a Progranulins: genetics
|2 MeSH
650 _ 2 |a Proteomics
|2 MeSH
650 _ 2 |a tau Proteins: genetics
|2 MeSH
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
700 1 _ |a Mol, Merel O
|b 1
700 1 _ |a Koopmans, Frank T W
|b 2
700 1 _ |a Hondius, David C
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700 1 _ |a van Nierop, Pim
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700 1 _ |a Menden, Kevin
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700 1 _ |a de Veij Mestdagh, Christina F
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700 1 _ |a van Rooij, Jeroen
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700 1 _ |a Ganz, Andrea B
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700 1 _ |a Paliukhovich, Iryna
|b 9
700 1 _ |a Melhem, Shamiram
|b 10
700 1 _ |a Li, Ka Wan
|b 11
700 1 _ |a Holstege, Henne
|b 12
700 1 _ |a Rizzu, Patrizia
|0 P:(DE-2719)2810718
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700 1 _ |a van Kesteren, Ronald E
|b 14
700 1 _ |a van Swieten, John C
|b 15
700 1 _ |a Heutink, Peter
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700 1 _ |a Smit, August B
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773 _ _ |a 10.1186/s40478-022-01387-8
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