%0 Journal Article
%A Ruf, Wolfgang P
%A Kühlwein, Julia
%A Meier, Laura
%A Tripke, Sarah
%A LeeBae, Jaehyun
%A Sadri-Vakili, Ghazaleh
%A Yilmazer-Hanke, Deniz
%A Petri, Susanne
%A Thal, Dietmar R
%A Grozdanov, Veselin
%A Danzer, Karin M
%T Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex.
%J Nature Communications
%V 17
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DZNE-2026-00277
%P 2406
%D 2026
%X Cytoplasmic TDP-43 pathology is a pathological sign of ALS/ALS-FTD and a converging disease event across different genotypes, phenotypes and CNS areas. To understand this process and target it therapeutically, we need to define which cell types are affected and which cell-type specific effects make them particularly vulnerable. We coupled flow-cytometry nuclear sorting and sequencing with single-nucleus multi-omic ATAC-seq and RNA-seq and spatial transcriptomics to define the transcriptional cell type of affected neurons in the post-mortem ALS/ALS-FTD motor cortex (30 ALS, 20 ALS-FTD </td><td width="150">
%X  32 control samples). Here, we show that mainly excitatory cortical neurons are affected by TDP-43 pathology and define the cell types that are affected the most: intratelencephalic L2-L3-LINC00507-FREM3, L3-L5-RORB-LNX2, L3-L5-RORB-ADGRL4 </td><td width="150">
%X  L6-THEMIS-LINC00343 neurons and extratelencephalic L5-FEZF2-NTNG1 neurons. Transcriptional aberrations by TDP-43 pathology, like cryptic exon inclusion, are cell-type specific and affect distinct gene sets in each cell type, highlighting the need to address TDP-43 pathology in a cell-type specific manner.
%K Motor Cortex: pathology
%K Motor Cortex: metabolism
%K Humans
%K DNA-Binding Proteins: metabolism
%K DNA-Binding Proteins: genetics
%K Amyotrophic Lateral Sclerosis: pathology
%K Amyotrophic Lateral Sclerosis: genetics
%K Amyotrophic Lateral Sclerosis: metabolism
%K Male
%K Neurons: metabolism
%K Neurons: pathology
%K Female
%K Frontotemporal Dementia: pathology
%K Frontotemporal Dementia: genetics
%K Frontotemporal Dementia: metabolism
%K Aged
%K Middle Aged
%K Transcriptome
%K DNA-Binding Proteins (NLM Chemicals)
%K TARDBP protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41803120
%R 10.1038/s41467-026-69944-6
%U https://pub.dzne.de/record/285638