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024 7 _ |a 10.1038/s41467-026-69944-6
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100 1 _ |a Ruf, Wolfgang P
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245 _ _ |a Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex.
260 _ _ |a [London]
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|b Springer Nature
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520 _ _ |a 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.
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650 _ 7 |a DNA-Binding Proteins
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650 _ 7 |a TARDBP protein, human
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650 _ 2 |a Motor Cortex: pathology
|2 MeSH
650 _ 2 |a Motor Cortex: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: pathology
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Neurons: pathology
|2 MeSH
650 _ 2 |a Female
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650 _ 2 |a Frontotemporal Dementia: pathology
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: genetics
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650 _ 2 |a Frontotemporal Dementia: metabolism
|2 MeSH
650 _ 2 |a Aged
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650 _ 2 |a Middle Aged
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650 _ 2 |a Transcriptome
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700 1 _ |a Kühlwein, Julia
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700 1 _ |a Meier, Laura
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700 1 _ |a Tripke, Sarah
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700 1 _ |a LeeBae, Jaehyun
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700 1 _ |a Sadri-Vakili, Ghazaleh
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700 1 _ |a Yilmazer-Hanke, Deniz
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700 1 _ |a Petri, Susanne
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700 1 _ |a Thal, Dietmar R
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700 1 _ |a Grozdanov, Veselin
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700 1 _ |a Danzer, Karin M
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773 _ _ |a 10.1038/s41467-026-69944-6
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