Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia.
Cell type enrichment
Frontotemporal dementia
GRN
Human brain proteomics
MAPT
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
07 07 2022
07 07 2022
Historique:
received:
05
04
2022
accepted:
22
05
2022
entrez:
7
7
2022
pubmed:
8
7
2022
medline:
12
7
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35799292
doi: 10.1186/s40478-022-01387-8
pii: 10.1186/s40478-022-01387-8
pmc: PMC9261008
doi:
Substances chimiques
GRN protein, human
0
Intercellular Signaling Peptides and Proteins
0
MAPT protein, human
0
Progranulins
0
tau Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
100Informations de copyright
© 2022. The Author(s).
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