Transcriptomic signature of frontotemporal lobar degeneration with TDP-43 type C pathology.

Overview

1. Department of Neurology and Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam 3015 GD, The Netherlands
2. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam 3015 GD, The Netherlands
3. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3015 GD, The Netherlands

Abstract

The semantic variant of primary progressive aphasia is a clinical subtype of frontotemporal lobar degeneration and is marked by TDP-43 subtype C pathology (FTLD-TDP C). It is a sporadic disease, yet has a strikingly homogeneous clinicopathological presentation, suggesting a common pathophysiology. The aim of this study was to discover dysregulated pathways in FTLD-TDP C through transcriptomics of the temporal cortex—its most affected region.

Bulk RNA sequencing was conducted on temporal cortices of a post-mortem cohort of 18 FTLD-TDP C patients and 23 sex- and age-matched controls. Differential expression and functional analyses were performed to identify differentially expressed genes [DEGs; false discovery rate (FDR) < 0.05] and functionally annotate them. We assessed the enrichment of TARDBP’s protein interactors and RNA targets among the DEGs. Our findings were compared with other published RNA sequencing data on tauopathies (Alzheimer’s dementia, progressive supranuclear palsy and FTLD with MAPT), FTLD-TDP (subtypes A and B) and available proteomics from this cohort. Additionally, we performed a weighted gene co-expression network analysis (WGCNA), adjusting for differences in cell type composition between cases and controls using cell deconvolution, and removing genes dysregulated in temporal cortices identified in other datasets. Among the FTLD-TDP DEGs, we focused on the enrichment of synaptic processes using SynGO.

We found upregulation of (i) damage response, (ii) cell structure and (iii) RNA splicing processes, and (iv) downregulation of synaptic processes in 6322 DEGs and five disease-related WGCNA modules. TARDBP-related genes were enriched among the DEGs. Additionally, transmembrane transport across the neurovascular unit was dysregulated. After cell deconvolution and removal of common tau genes, postsynaptic processes remained dysregulated, specifically the gene ontology terms ‘modulation of chemical synaptic transmission’ and ‘neurotransmitter receptor localization to postsynaptic specialization membrane’. We found 11 synaptic FTLD-TDP C-specific genes affected at both the RNA and protein levels in the temporal cortex, which were involved in synaptic adhesion (CADM1, NCAN), signal transmission (COMT, RGS144, SLC1A2, TUBB2B) and synaptic plasticity (BEGAIN, ITPKA, LRFN1, RAB3B, SYNPO).

In conclusion, a wide range of processes were dysregulated at the RNA level in the temporal cortex of FTLD-TDP C, including commonly affected processes in neurodegeneration, such as structural cell alterations. Dysregulation of TARDBP-related genes and RNA splicing has also been observed in other TDP-43 proteinopathies. Importantly, we found that postsynaptic processes were downregulated in FTLD-TDP C, after removing tauopathy-related genes and after cell deconvolution. In particular, the assembly of receptors at the postsynaptic membrane and synaptic signal transmission were affected, both at the RNA and protein levels. Future research on these pathways could elucidate distinct pathophysiological mechanisms and guide targeted clinical approaches.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data and to no code of its authors: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• portal.brain-map.org/atlases-and-data/rnaseq, at Allen Brain Map; found in the references

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary material.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 4 November 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 4 keywords, 13 MeSH terms, 2 funders, 0 references.

Cite

This paper

Rajicic, A., Mol, M. O., Melhem, S., Kisic, H., van Swieten, J. C., Seelaar, H., & van Rooij, J. G. J. (2026). Transcriptomic signature of frontotemporal lobar degeneration with TDP-43 type C pathology. Brain : a journal of neurology, 149(11), 3875-3889. https://doi.org/10.1093/brain/awag085

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1186/s13024-025-00869-2

Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes.

Journal: Molecular neurodegeneration

In common: Alzheimer's / dementia, genetics / omics, 3 authors

[2] doi:10.1038/s41467-025-59216-0

Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.

Journal: Nature communications

In common: Alzheimer's / dementia, genetics / omics, 3 authors

[3] doi:10.1186/s40478-025-02077-x

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

Journal: Acta neuropathologica communications

In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, author Jeroen G J van Rooij

[4] doi:10.1186/s40478-022-01387-8

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

Journal: Acta neuropathologica communications

In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, author Jeroen G J van Rooij

[5] doi:10.1007/s00401-022-02454-z [code]

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.

Journal: Acta neuropathologica

In common: Alzheimer's / dementia, genetics / omics, author Merel O Mol

[6] doi:10.1093/brain/awaf443 [code]

Cellular signatures underlying functional resilience in presymptomatic frontotemporal dementia.

Journal: Brain : a journal of neurology

In common: Alzheimer's / dementia, genetics / omics, author Harro Seelaar

[7] doi:10.1038/s41467-026-71682-8 [code]

GWAS meta-analysis of cerebrospinal fluid Alzheimer's biomarkers reveals loci regulating lipids, brain volume and autophagy.

Journal: Nature communications

In common: Alzheimer's / dementia, genetics / omics, author Harro Seelaar

[8] doi:10.1093/brain/awac069 [code]

Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia.

Journal: Brain : a journal of neurology

In common: Alzheimer's / dementia, genetics / omics, author Harro Seelaar

[9] doi:10.1093/brain/awac043

Psychiatric symptoms of frontotemporal dementia and subcortical (co-)pathology burden: new insights.

Journal: Brain : a journal of neurology

In common: Alzheimer's / dementia, author Merel O Mol

[10] doi:10.1038/s41380-025-03280-x [code]

Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study.

Journal: Molecular psychiatry

In common: Alzheimer's / dementia, author Harro Seelaar

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.

Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.