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

Abstract

Background Frontotemporal lobar degeneration (FTLD) is characterized pathologically by neuronal and glial inclusions of hyperphosphorylated tau or by neuronal cytoplasmic inclusions of TDP43. This study aimed at deciphering the molecular mechanisms leading to these distinct pathological subtypes. Methods To this end, we performed an unbiased mass spectrometry-based proteomic and systems-level analysis of the middle frontal gyrus cortices of FTLD-tau (n = 6), FTLD-TDP (n = 15), and control patients (n = 5). We validated these results in an independent patient cohort (total n = 24). Results The middle frontal gyrus cortex proteome was most significantly altered in FTLD-tau compared to controls (294 differentially expressed proteins at FDR = 0.05). The proteomic modifications in FTLD-TDP were more heterogeneous (49 differentially expressed proteins at FDR = 0.1). Weighted co-expression network analysis revealed 17 modules of co-regulated proteins, 13 of which were dysregulated in FTLD-tau. These modules included proteins associated with oxidative phosphorylation, scavenger mechanisms, chromatin regulation, and clathrin-mediated transport in both the frontal and temporal cortex of FTLD-tau. The most strongly dysregulated subnetworks identified cyclin-dependent kinase 5 (CDK5) and polypyrimidine tract-binding protein 1 (PTBP1) as key players in the disease process. Dysregulation of 9 of these modules was confirmed in independent validation data sets of FLTD-tau and control temporal and frontal cortex (total n = 24). Dysregulated modules were primarily associated with changes in astrocyte and endothelial cell protein abundance levels, indicating pathological changes in FTD are not limited to neurons. Conclusions Using this innovative workflow and zooming in on the most strongly dysregulated proteins of the identified modules, we were able to identify disease-associated mechanisms in FTLD-tau with high potential as biomarkers and/or therapeutic targets.

High-plex Digital Spatial Profiling Identifies Subregion-Dependent Directed Proteome Changes Across Multiple Variants of Dementia

“…These data reveal that phosphorylated tau protein deposits are likely unique to cortical and subcortical subregion. Although there is substantial evidence of various phosphorylated tau protein deposition in multiple regions of the brains of FTLD patients [23,24,25], our data further solidify that phosphorylated tau may be subregion dependent within the human cortical and subcortical brain layers.…”

Frontotemporal Dementia, Where Do We Stand? A Narrative Review

“…Therefore, despite the negative result so far, it is possible that further studies may demonstrate the superiority of some tau fragments over others in the diagnosis of FTD. Finally, very interestingly, to investigate the molecular mechanisms responsible for the different pathological accumulations of FTLD, recent work has used a mass-spectrometry-based proteomic and systems-level analysis of the middle frontal gyrus cortices, highlighting cyclin-dependent kinase 5 and polypyrimidine-tract-binding protein 1 as key players in the disease process [227]. Of note, the pathological alterations were associated with changes in astrocyte and endothelial cell protein abundance levels, highlighting that the changes typical of the disease are not limited to neurons and that glial cells may also provide valuable information on the pathophysiology of FTD.…”