ArticleAlzheimer's research & therapy2023
Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration.
Article in Alzheimer's research & therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 9 citations in OpenAlex.
- Membrane-associated Rhes-Slc4a7 complex orchestrates tunneling nanotube formation and mutant Huntingtin spread.Science advances · 2026Article
- Exploring the PLD1-tau interaction in Frontotemporal Dementia.bioRxiv : the preprint server for biology · 2026Article
- Distinct cerebrospinal fluid proteomic signatures define clinicopathological subtypes of sporadic Creutzfeldt-Jakob disease and predict patient survival.Acta neuropathologica communications · 2025Article
- Proteomics of the temporal cortex in semantic dementia reveals brain-region specific molecular pathology and regulation of the TDP-43-ANXA11 interactome.Acta neuropathologica communications · 2025Article
- Synapse vulnerability and resilience across the clinical spectrum of dementias.Nature reviews. Neurology · 2025Review
- Multiplex digital spatial profiling identifies subregion dependent targeted proteome changes across variants of dementia.NPJ dementia · 2025Article
- Proteomic networks of gray and white matter reveal tissue-specific changes in human tauopathy.Annals of clinical and translational neurology · 2024Article
- Frontotemporal Dementia, Where Do We Stand? A Narrative Review.International journal of molecular sciences · 2023Review
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundFrontotemporal 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.
methodsTo 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).
resultsThe 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.
conclusionsUsing 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.
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