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Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia
- Source :
- Acta Neuropathologica Communications, 10:100, 1-20. BioMed Central, Acta Neuropathologica Communications 10, 100 (2022). doi:10.1186/s40478-022-01387-8, Acta neuropathologica communications, 10(1):100. BioMed Central, Miedema, S S M, Mol, M O, Koopmans, F T W, Hondius, D C, van Nierop, P, Menden, K, de Veij Mestdagh, C F, van Rooij, J, Ganz, A B, Paliukhovich, I, Melhem, S, Li, K W, Holstege, H, Rizzu, P, van Kesteren, R E, van Swieten, J C, Heutink, P & Smit, A B 2022, ' Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia ', Acta neuropathologica communications, vol. 10, no. 1, 100 . https://doi.org/10.1186/s40478-022-01387-8, Miedema, S S M, Mol, M O, Koopmans, F T W, Hondius, D C, van Nierop, P, Menden, K, de Veij Mestdagh, C F, van Rooij, J, Ganz, A B, Paliukhovich, I, Melhem, S, Li, K W, Holstege, H, Rizzu, P, van Kesteren, R E, van Swieten, J C, Heutink, P & Smit, A B 2022, ' Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia ', Acta Neuropathologica Communications, vol. 10, 100, pp. 1-20 . https://doi.org/10.1186/s40478-022-01387-8, Acta neuropathologica communications, 10(1):100. BioMed Central Ltd.
- Publication Year :
- 2022
- Publisher :
- BioMed Central Ltd., 2022.
-
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.
- Subjects :
- Proteomics
genetics [Mutation]
MAPT protein, human
tau Proteins
Pathology and Forensic Medicine
genetics [Progranulins]
Cellular and Molecular Neuroscience
Progranulins
Pick Disease of the Brain
metabolism [Endothelial Cells]
MAPT
Humans
ddc:610
genetics [Frontotemporal Dementia]
genetics [Intercellular Signaling Peptides and Proteins]
Cell type enrichment
Endothelial Cells
metabolism [tau Proteins]
genetics [tau Proteins]
Mutation
pathology [Frontotemporal Dementia]
GRN protein, human
Human brain proteomics
Intercellular Signaling Peptides and Proteins
Neurology (clinical)
Frontotemporal dementia
GRN
Subjects
Details
- Language :
- English
- ISSN :
- 20515960
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Acta neuropathologica communications
- Accession number :
- edsair.doi.dedup.....16ed3f5c28d1f7163a6a79c1cdeb0f90