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000164917 037__ $$aDZNE-2022-01328
000164917 041__ $$aEnglish
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000164917 1001_ $$aMiedema, Suzanne S M$$b0
000164917 245__ $$aDistinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia.
000164917 260__ $$aLondon$$bBiomed Central$$c2022
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000164917 520__ $$aFrontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer's disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.
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000164917 650_7 $$2Other$$aCell type enrichment
000164917 650_7 $$2Other$$aFrontotemporal dementia
000164917 650_7 $$2Other$$aGRN
000164917 650_7 $$2Other$$aHuman brain proteomics
000164917 650_7 $$2Other$$aMAPT
000164917 650_7 $$2NLM Chemicals$$aGRN protein, human
000164917 650_7 $$2NLM Chemicals$$aIntercellular Signaling Peptides and Proteins
000164917 650_7 $$2NLM Chemicals$$aMAPT protein, human
000164917 650_7 $$2NLM Chemicals$$aProgranulins
000164917 650_7 $$2NLM Chemicals$$atau Proteins
000164917 650_2 $$2MeSH$$aEndothelial Cells: metabolism
000164917 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000164917 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000164917 650_2 $$2MeSH$$aHumans
000164917 650_2 $$2MeSH$$aIntercellular Signaling Peptides and Proteins: genetics
000164917 650_2 $$2MeSH$$aMutation: genetics
000164917 650_2 $$2MeSH$$aPick Disease of the Brain
000164917 650_2 $$2MeSH$$aProgranulins: genetics
000164917 650_2 $$2MeSH$$aProteomics
000164917 650_2 $$2MeSH$$atau Proteins: genetics
000164917 650_2 $$2MeSH$$atau Proteins: metabolism
000164917 7001_ $$aMol, Merel O$$b1
000164917 7001_ $$aKoopmans, Frank T W$$b2
000164917 7001_ $$aHondius, David C$$b3
000164917 7001_ $$avan Nierop, Pim$$b4
000164917 7001_ $$0P:(DE-2719)2812499$$aMenden, Kevin$$b5$$udzne
000164917 7001_ $$ade Veij Mestdagh, Christina F$$b6
000164917 7001_ $$avan Rooij, Jeroen$$b7
000164917 7001_ $$aGanz, Andrea B$$b8
000164917 7001_ $$aPaliukhovich, Iryna$$b9
000164917 7001_ $$aMelhem, Shamiram$$b10
000164917 7001_ $$aLi, Ka Wan$$b11
000164917 7001_ $$aHolstege, Henne$$b12
000164917 7001_ $$0P:(DE-2719)2810718$$aRizzu, Patrizia$$b13$$udzne
000164917 7001_ $$avan Kesteren, Ronald E$$b14
000164917 7001_ $$avan Swieten, John C$$b15
000164917 7001_ $$0P:(DE-2719)2810728$$aHeutink, Peter$$b16$$udzne
000164917 7001_ $$aSmit, August B$$b17
000164917 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-022-01387-8$$gVol. 10, no. 1, p. 100$$p100$$tActa Neuropathologica Communications$$v10$$x2051-5960$$y2022
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