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.
Original language | English |
---|---|
Article number | 100 |
Pages (from-to) | 1-20 |
Number of pages | 20 |
Journal | Acta Neuropathologica Communications |
Volume | 10 |
DOIs | |
Publication status | Published - 7 Jul 2022 |
Bibliographical note
Funding Information:This work was supported by Risk and Modifying factors for Fronto-Temporal Dementia (RiMod-FTD), an EU Joint Programme–Neurodegenerative Disease Research (JPND) funded project, and the NOMIS Foundation. The RiMod-FTD consortium contributed to the design of the study and the collection of post-mortem brain materials.
Funding Information:
This is an EU Joint Programme—Neurodegenerative Disease Research (JPND) project. Brain tissues for this study were obtained from the Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands and the Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London, UK. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology
Funding Information:
This is an EU Joint Programme—Neurodegenerative Disease Research (JPND) project. Brain tissues for this study were obtained from the Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands and the Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London, UK. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology
Publisher Copyright:
© 2022, The Author(s).
Keywords
- Cell type enrichment
- Frontotemporal dementia
- GRN
- Human brain proteomics
- MAPT
Fingerprint
Dive into the research topics of 'Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia'. Together they form a unique fingerprint.Datasets
-
Additional file 3 of Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia
Miedema, S. (Creator), Mol, M. O. (Creator), Koopmans, F. (Creator), Hondius, D. C. (Creator), van Nierop, P. (Creator), Menden, K. (Creator), de Veij Mestdagh, C. F. (Creator), van Rooij, J. (Creator), Ganz, A. B. (Creator), Paliukhovich, I. (Creator), Melhem, S. (Creator), Li, K. W. (Creator), Holstege, H. (Creator), Rizzu, P. (Creator), van Kesteren, R. (Creator), van Swieten, J. C. (Creator), Heutink, P. (Creator) & Smit, G. (Creator), Figshare, 2022
DOI: 10.6084/m9.figshare.20267353.v1, https://springernature.figshare.com/articles/dataset/Additional_file_3_of_Distinct_cell_type-specific_protein_signatures_in_GRN_and_MAPT_genetic_subtypes_of_frontotemporal_dementia/20267353/1
Dataset / Software: Dataset
-
Additional file 13 of Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia
Miedema, S. (Creator), Mol, M. O. (Creator), Koopmans, F. (Creator), Hondius, D. C. (Creator), van Nierop, P. (Creator), Menden, K. (Creator), de Veij Mestdagh, C. F. (Creator), van Rooij, J. (Creator), Ganz, A. B. (Creator), Paliukhovich, I. (Creator), Melhem, S. (Creator), Li, K. W. (Creator), Holstege, H. (Creator), Rizzu, P. (Creator), van Kesteren, R. (Creator), van Swieten, J. C. (Creator), Heutink, P. (Creator) & Smit, G. (Creator), Figshare, 2022
DOI: 10.6084/m9.figshare.20267332.v1, https://springernature.figshare.com/articles/dataset/Additional_file_13_of_Distinct_cell_type-specific_protein_signatures_in_GRN_and_MAPT_genetic_subtypes_of_frontotemporal_dementia/20267332/1
Dataset / Software: Dataset
-
Additional file 7 of Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia
Miedema, S. (Creator), Mol, M. O. (Creator), Koopmans, F. (Creator), Hondius, D. C. (Creator), van Nierop, P. (Creator), Menden, K. (Creator), de Veij Mestdagh, C. F. (Creator), van Rooij, J. (Creator), Ganz, A. B. (Creator), Paliukhovich, I. (Creator), Melhem, S. (Creator), Li, K. W. (Creator), Holstege, H. (Creator), Rizzu, P. (Creator), van Kesteren, R. (Creator), van Swieten, J. C. (Creator), Heutink, P. (Creator) & Smit, G. (Creator), Figshare, 2022
DOI: 10.6084/m9.figshare.20267365.v1, https://springernature.figshare.com/articles/dataset/Additional_file_7_of_Distinct_cell_type-specific_protein_signatures_in_GRN_and_MAPT_genetic_subtypes_of_frontotemporal_dementia/20267365/1
Dataset / Software: Dataset