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.