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

Topic: Brain proteins, microglia and lab models

Our findings were compared to other published RNA sequencing data of tauopathies (Alzheimer's dementia, progressive supranuclear palsy and FTLD with MAPT), FTLD-TDP (subtypes A&B) and available proteomics of this cohort. We found upregulation of damage response, cell structure, RNA splicing processes and downregulation of synaptic processes in 6322 DEG and five disease-related WGCNA modules. We found eleven synaptic FTLD-TDP C-specific genes affected on both RNA- and protein-level 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 on RNA-level in the temporal cortex of FTLD-TDP C, including commonly affected processes in neurodegeneration, such as structural cell alterations. Importantly, we found that postsynaptic processes were downregulated in FTLD-TDP C, after removing tauopathy-related genes and after cell deconvolution.

@article{rajicic2026-41789476,
  author  = {Rajicic, Ana and Mol, Merel O. and Melhem, Shamiram and Kisic, Helena and Van Swieten, John Cornelis and Seelaar, Harro and van Rooij, Jeroen},
  title   = {{Transcriptomic signature of frontotemporal lobar degeneration with TDP-43 type C pathology}},
  journal = {Brain},
  year    = {2026},
  doi     = {10.1093/brain/awag085},
  pmid    = {41789476},
  url     = {https://doi.org/10.1093/brain/awag085}
}

Key findings

• Our findings were compared to other published RNA sequencing data of tauopathies (Alzheimer's dementia, progressive supranuclear palsy and FTLD with MAPT), FTLD-TDP (subtypes A&B) and available proteomics of this cohort.
• We found upregulation of damage response, cell structure, RNA splicing processes and downregulation of synaptic processes in 6322 DEG and five disease-related WGCNA modules.
• We found eleven synaptic FTLD-TDP C-specific genes affected on both RNA- and protein-level 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 on RNA-level in the temporal cortex of FTLD-TDP C, including commonly affected processes in neurodegeneration, such as structural cell alterations.
• Importantly, we found that postsynaptic processes were downregulated in FTLD-TDP C, after removing tauopathy-related genes and after cell deconvolution.

Why it matters

This study analyzed RNA and protein in the temporal cortex of frontotemporal lobar degeneration with TDP-43 type C pathology, finding upregulation of damage response, cell structure and RNA splicing processes and downregulation of synaptic processes, including eleven synaptic genes affected at both RNA and protein level. It describes disease-related molecular changes and does not test any treatment, cure or prevention.

Study details

• Evidence strengthModerate

Read the original

• DOI: 10.1093/brain/awag085
• PubMed: 41789476
• Original source →
• Free full text: Brain →

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