Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia

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.

Proteomics of the dentate gyrus reveals semantic dementia specific molecular pathology

“…Functional enrichment analysis of the 151 differentially expressed proteins in SD indicated changes also previously reported in cortical brain regions affected by TDP-43 and AD pathology such as immune response activation, astrogliosis, cellular adhesion, and metabolic processes [ 17 – 19 , 31 , 32 ], likely reflecting general neurodegenerative changes. The identification of these established pathways confirms that our proteomic strategy detects the global processes affected or caused by neuronal loss.…”

“…In contrast to the comprehensive histological characterization [ 10 ], relatively few studies applied MS on FTLD-TDP brain tissue [ 16 ]. Two studies identified abnormal protein abundances involving neuroinflammation, RNA processing, protein metabolism, and synaptic transmission [ 17 , 18 ], and a recent report described the proteomic signatures and cell types involved in genetic FTLD [ 19 ]. One of the greatest challenges in brain tissue proteomics lies in the identification of specific disease processes, as the aforementioned pathways are typically observed in many different brain disorders and may represent coinciding neurodegenerative changes.…”

Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration

“…The second data set consisted of proteomic abundance data of the microdissected temporal cortex originating from 13 autosomal dominant fFTD individuals with FTLD-tau underlying pathology and 8 NHC (Table S 1 ). These data sets were selected from a larger data set that was acquired following the same brain sample preparation protocol, protein-to-peptide procedure, proteomic workflow, and instruments as in this study, but analysed in a different batch [ 18 ]. Access to the full data set of the validation cohort is provided in the original publication [ 18 ].…”

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration

“…Concerning FTLD, a decreased expression of a mitochondrial module in frontal cortex tissue from FTD-TDP patients was reported [ 48 ], and a very recent study has shown that in brains of FTD patients carrying different GRN mutations, mitochondrial dysregulation is detected in neurons at variance with MAPT mutations carriers, where other cellular processes are affected [ 49 ]. In particular, proteins of the oxidoreductase complex are down-regulated, especially those of respiratory chain complex 1.…”