Single-cell dissection of the primary motor cortex in ALS and FTLD patients.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable and fatal neurodegenerative conditions. While distinct, they share many clinical, genetic, and pathological characteristics, and both show highly vulnerable layer 5 extratelencephalic-projecting cortical populations, including Betz cells in ALS2 and von Economo neurons (VENs) in FTLD. Here, we report the first single-cell atlas of the human primary motor cortex and its changes in ALS and FTLD across ~380,000 nuclei from 64 control, sporadic and C9orf72-associated ALS and FTLD individuals. We identify 46 transcriptionally distinct cellular subtypes including two Betz-cell subtypes, and observe a previously-unappreciated molecular similarity between Betz cells and VENs of the frontal insula. Most dysregulated genes and pathways were shared, including stress response, ribosome function, oxidative phosphorylation, synaptic vesicle cycle, endoplasmic reticulum protein processing, and autophagy. Betz cells and SCN4B+ long-range projecting L3/L5 cells are the most transcriptionally affected in both ALS and FTLD. Lastly, the VEN/Betz-cell-enriched dysregulated gene POU3F1 co-localizes with TDP-43 aggregates in Betz cells. Overall design: Single-nucleus RNA-seq profiling of the human primary motor cortex in amyotrophic lateral sclerosis and frontotemporal lobar degeneration **This dataset has been replaced by BioProject PRJNA1073234**