Dataset Information

Proteomics of the temporal cortex in Semantic Dementia reveals brain-region specific molecular pathology and regulation of the TDP-43-ANXA11 interactome

ABSTRACT: Semantic dementia (SD) is a clinical subtype of frontotemporal dementia characterized by impaired word comprehension and semantic memory, and occurs nearly always sporadically. Neuroimaging typically reveals asymmetric, predominantly left-sided, atrophy of the anterior temporal pole, anterior fusiform gyrus, and the hippocampus. Post-mortem pathological examination shows frontotemporal lobar degeneration TDP type C, characterized by long dystrophic neurites in the temporal cortex and typical round, TDP-43-positive neuronal inclusions in the dentate gyrus. While neuronal loss in the temporal cortex is severe in the end stage of disease, the dentate gyrus seems relatively spared. This characteristic and well-defined disease profile suggests SD patients share a specific underlying disease biology. Recently, we performed the first quantitative proteomic study of the dentate gyrus, uncovering potential SD-specific biological pathways. Here, we report on the first quantitative proteomic study of the temporal cortex in SD. We studied the same patient and non-demented control cohort, enabling comparative analysis between the two brain regions. In addition, we compared our dataset with other frontotemporal lobar degeneration subtypes and Alzheimer’s disease to separate SD disease-specific changes from common neurodegenerative processes. In the temporal cortex, involvement of the ribonucleoprotein complex and presynaptic regulation of cytosolic calcium levels by voltage-gated calcium channels appear unique facets of the SD disease process. Furthermore, we observed a striking difference in the abundance of neuropathological proteins TDP-43 and ANXA11, and their interactors between the temporal cortex and dentate gyrus. The elucidation of these potentially unique disease-specific mechanisms improves our understanding of the pathophysiological processes in SD and paves the way for the discovery of novel therapeutic targets.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Semantic Dementia

SUBMITTER: Suzanne Miedema

LAB HEAD: A.B. Smit

PROVIDER: PXD062722 | Pride | 2026-01-16

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20210407_198_029_GTS_SD_37.wiff	Wiff
	20210407_198_029_GTS_SD_37.wiff.scan	Wiff
	20210407_1994_116_GTM_NDC_15.wiff	Wiff
	20210407_1994_116_GTM_NDC_15.wiff.scan	Wiff
	20210407_1994_339_158C_NDC_10.wiff	Wiff

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Publications

Proteomics of the temporal cortex in semantic dementia reveals brain-region specific molecular pathology and regulation of the TDP-43-ANXA11 interactome.

Miedema Suzanne S M SSM Rajicic Ana A Mol Merel O MO Paliukhovich Iryna I Klaassen Remco V RV van Buuren Renee R Li Ka Wan KW Koopmans Frank T W FTW Seelaar Harro H van Rooij Jeroen G J JGJ Smit August B AB van Swieten John C JC

Acta neuropathologica communications 20250725 1

Semantic dementia (SD) is a clinical subtype of frontotemporal dementia characterized by impaired word comprehension and semantic memory, and occurs nearly always sporadically. Neuroimaging typically reveals asymmetric, predominantly left-sided, atrophy of the anterior temporal pole, anterior fusiform gyrus, and the hippocampus. Post-mortem pathological examination shows frontotemporal lobar degeneration TDP type C, characterized by long dystrophic neurites in the temporal cortex and typical rou ...[more]

PMID: 40713859

Publication: 1/2

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Project description:Background Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by language deficits due to severe temporal lobe degeneration. The consistent neuropathological diagnosis is FTD-TDP subtype C, with characteristic round TDP-43 protein inclusions in the dentate gyrus. Despite this striking clinicopathological concordance, the pathogenic mechanisms are largely unexplained forestalling the development of targeted therapeutics. Methods We carried out laser capture microdissection of the dentate gyrus of 15 SD patients and 17 non-demented controls, and assessed relative protein abundance changes by label-free quantitative mass spectrometry. To identify SD specific proteins, we compared our results to eight other FTD and Alzheimer’s disease (AD) proteomic datasets of cortical brain tissue, parallel with functional enrichment analyses and protein-protein interactions (PPI). Results Of the total 5,354 quantified proteins, 151 showed differential abundance (FDR<1%) in SD patients. Seventy-two proteins were previously found altered with the same directional change in at least one FTD/AD proteomic study, while 79 proteins were considered as showing potentially SD specific dysregulation. Functional enrichment indicated an overrepresentation of pathways related to the immune response, metabolic processes, and cell-junction assembly. PPI analysis highlighted a cluster of interacting proteins associated with adherens junction and cadherin binding– the cadherin-catenin complex. Multiple proteins in this complex showed strong and apparent specific upregulation in SD, including β-catenin (CTNNB1), γ-catenin (JUP), and N-cadherin (CDH2). Conclusions We discovered an increase of cell adhesion proteins in SD specifically constituting the cadherin-catenin complex at the synaptic membrane, essential for synaptic signaling. Although further validation is warranted, we anticipate that these findings will help unravel the disease processes underlying SD.