TY  - JOUR
AU  - Miedema, Suzanne S M
AU  - Mol, Merel O
AU  - Koopmans, Frank T W
AU  - Hondius, David C
AU  - van Nierop, Pim
AU  - Menden, Kevin
AU  - de Veij Mestdagh, Christina F
AU  - van Rooij, Jeroen
AU  - Ganz, Andrea B
AU  - Paliukhovich, Iryna
AU  - Melhem, Shamiram
AU  - Li, Ka Wan
AU  - Holstege, Henne
AU  - Rizzu, Patrizia
AU  - van Kesteren, Ronald E
AU  - van Swieten, John C
AU  - Heutink, Peter
AU  - Smit, August B
TI  - Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia.
JO  - Acta Neuropathologica Communications
VL  - 10
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DZNE-2022-01328
SP  - 100
PY  - 2022
N1  - CC BY
AB  - 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.
KW  - Endothelial Cells: metabolism
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: pathology
KW  - Humans
KW  - Intercellular Signaling Peptides and Proteins: genetics
KW  - Mutation: genetics
KW  - Pick Disease of the Brain
KW  - Progranulins: genetics
KW  - Proteomics
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - Cell type enrichment (Other)
KW  - Frontotemporal dementia (Other)
KW  - GRN (Other)
KW  - Human brain proteomics (Other)
KW  - MAPT (Other)
KW  - GRN protein, human (NLM Chemicals)
KW  - Intercellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Progranulins (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35799292
C2  - pmc:PMC9261008
DO  - DOI:10.1186/s40478-022-01387-8
UR  - https://pub.dzne.de/record/164917
ER  -