Journal Article

DZNE-2026-00277

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex.

Ruf, W. P. (First author)DZNE* ; Kühlwein, J.Extern* ; Meier, L.Extern* ; Tripke, S.Extern* ; LeeBae, J.DZNE* ; Sadri-Vakili, G. ; Yilmazer-Hanke, D. ; Petri, S. ; Thal, D. R. ; Grozdanov, V.Extern* ; Danzer, K. M. (Last author)DZNE*

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-026-69944-6

Abstract: 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 & 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 & 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.

Keyword(s): Motor Cortex: pathology (MeSH) ; Motor Cortex: metabolism (MeSH) ; Humans (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Male (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Female (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: metabolism (MeSH) ; Aged (MeSH) ; Middle Aged (MeSH) ; Transcriptome (MeSH) ; DNA-Binding Proteins ; TARDBP protein, human

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Contributing Institute(s):

1. Mechanisms of Propagation (AG Danzer)
2. Clinical Study Center (Ulm) (Clinical Study Center (Ulm))

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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