Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex

TL;DR

The study identifies specific neurons in the motor cortex affected by TDP-43 pathology in ALS/ALS-FTD and shows that gene changes are unique to each neuron type.

Contribution

The paper identifies cell-type specific effects of TDP-43 pathology in the motor cortex using multi-omic and spatial methods.

Findings

Excitatory cortical neurons are mainly affected by TDP-43 pathology in ALS/ALS-FTD.

Transcriptional changes like cryptic exon inclusion are cell-type specific and affect distinct gene sets.

Specific neuron subtypes such as intratelencephalic and extratelencephalic neurons are most affected.

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.

TDP-43 pathology is a key event in ALS/FTD and selectively affects specific neurons in the motor cortex. Here, the authors report which neuron types are affected and demonstrate that transcriptomic changes are cell-type specific.

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