Overview
- Researchers profiled post-mortem motor cortex from about 80 donors across Germany, the Netherlands, Scotland and the United States using flow-cytometry nuclear sorting, single-nucleus multi-omic ATAC/RNA-seq and spatial transcriptomics.
- TDP-43 aggregates were found to occur predominantly in excitatory neurons that transmit and amplify signals, with inhibitory neurons less affected.
- The team identified five selectively vulnerable neuronal subtypes with distinct transcriptional signatures, comprising four intratelencephalic groups and one extratelencephalic group.
- Cell-type-specific molecular disruptions, including cryptic exon inclusion, differed across the vulnerable subtypes.
- Authors describe the cell-level map as a roadmap for cell-type-directed therapies and biomarkers, noting that functional validation and translational studies remain necessary.