A multi-omics characterization of the human lumbar spinal cord and motor cortex reveals non-overlapping molecular signatures in ALS [snRNA-Seq; snATAC-Seq]

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by the loss of upper and lower motor neurons in the motor cortex (MTC) and spinal cord (SC), respectively, leading to muscle atrophy and ultimately respiratory failure. While motor neurons (MNs) are the selectively vulnerable cell type, their interactions with glia contribute to the progression of ALS pathology. However, it remains unclear whether the molecular alterations underlying MN and glial dysfunction in ALS are the same in the MTC and lumbar SC (LSC). To address this, we constructed spatially-resolved gene expression maps of the MTC and LSC by combining spatial and single-nucleus transcriptomic profiles from a cohort of non-neurological controls and ALS patients clinically stratified by site of symptom onset. In the ventral horn of the LSC, we see a decrease in genes associated with MNs and synaptic signaling in ALS patients. We also identify region-specific alterations in endothelial- and glial-related functions. Notably, the severity of these MN deficits and endothelial-related functions is influenced by the site of symptom onset, whereas alterations in glial function largely are not. In the MTC, we observe layer-specific increases in synaptic signaling in ALS patients. Comparing the molecular and cellular changes within the LSC and MTC in ALS indicates that they are predominantly non-overlapping, and have different molecular signatures.