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000285638 1001_ $$0P:(DE-2719)9001522$$aRuf, Wolfgang P$$b0$$eFirst author$$udzne
000285638 245__ $$aMulti-modal dissection of cell-type specific TDP-43 pathology in the motor cortex.
000285638 260__ $$a[London]$$bSpringer Nature$$c2026
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000285638 520__ $$aCytoplasmic 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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000285638 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000285638 650_7 $$2NLM Chemicals$$aTARDBP protein, human
000285638 650_2 $$2MeSH$$aMotor Cortex: pathology
000285638 650_2 $$2MeSH$$aMotor Cortex: metabolism
000285638 650_2 $$2MeSH$$aHumans
000285638 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000285638 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000285638 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000285638 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000285638 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000285638 650_2 $$2MeSH$$aMale
000285638 650_2 $$2MeSH$$aNeurons: metabolism
000285638 650_2 $$2MeSH$$aNeurons: pathology
000285638 650_2 $$2MeSH$$aFemale
000285638 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000285638 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000285638 650_2 $$2MeSH$$aFrontotemporal Dementia: metabolism
000285638 650_2 $$2MeSH$$aAged
000285638 650_2 $$2MeSH$$aMiddle Aged
000285638 650_2 $$2MeSH$$aTranscriptome
000285638 7001_ $$0P:(DE-2719)9001523$$aKühlwein, Julia$$b1$$udzne
000285638 7001_ $$0P:(DE-2719)9002179$$aMeier, Laura$$b2$$udzne
000285638 7001_ $$0P:(DE-2719)9001521$$aTripke, Sarah$$b3$$udzne
000285638 7001_ $$0P:(DE-2719)9002103$$aLeeBae, Jaehyun$$b4
000285638 7001_ $$aSadri-Vakili, Ghazaleh$$b5
000285638 7001_ $$00000-0003-1483-0286$$aYilmazer-Hanke, Deniz$$b6
000285638 7001_ $$aPetri, Susanne$$b7
000285638 7001_ $$00000-0002-1036-1075$$aThal, Dietmar R$$b8
000285638 7001_ $$0P:(DE-2719)9001519$$aGrozdanov, Veselin$$b9$$udzne
000285638 7001_ $$0P:(DE-2719)9001513$$aDanzer, Karin M$$b10$$eLast author
000285638 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-026-69944-6$$gVol. 17, no. 1, p. 2406$$n1$$p2406$$tNature Communications$$v17$$x2041-1723$$y2026
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