TY  - JOUR
AU  - Ruf, Wolfgang P
AU  - Kühlwein, Julia
AU  - Meier, Laura
AU  - Tripke, Sarah
AU  - LeeBae, Jaehyun
AU  - Sadri-Vakili, Ghazaleh
AU  - Yilmazer-Hanke, Deniz
AU  - Petri, Susanne
AU  - Thal, Dietmar R
AU  - Grozdanov, Veselin
AU  - Danzer, Karin M
TI  - Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex.
JO  - Nature Communications
VL  - 17
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2026-00277
SP  - 2406
PY  - 2026
AB  - 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">
AB  -  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">
AB  -  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.
KW  - Motor Cortex: pathology
KW  - Motor Cortex: metabolism
KW  - Humans
KW  - DNA-Binding Proteins: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Male
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Female
KW  - Frontotemporal Dementia: pathology
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: metabolism
KW  - Aged
KW  - Middle Aged
KW  - Transcriptome
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - TARDBP protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41803120
DO  - DOI:10.1038/s41467-026-69944-6
UR  - https://pub.dzne.de/record/285638
ER  -