The Human Motoneuron Expression Signature is Defined by ALS-Related Genes

In neurodegenerative diseases of the human spinal cord, such as amyotrophic lateral sclerosis (ALS), motoneurons are particularly vulnerable to degeneration. It is hypothesized that their large size contributes to disease susceptibility, but the link between genetic variants associated with disease and cell-type specific degeneration is not clear. We characterized human spinal cord cells using single-nucleus RNA-sequencing and protein profiling. We found that human motoneurons displayed a unique expression profile characterized by factors involved in cytoskeletal structure, cell size, and degenerative disease (including ALS-associated genes SOD1, NEFH, OPTN, TUBA4A, PRPH, and STMN2) and that protein expression of these genes correlated with larger cell size in tissue. This work suggests a motoneuron-specific signature underlies their selective vulnerability to neurodegeneration. One-Sentence Summary Human spinal motoneurons preferentially express ALS genes, providing an explanation for their selective vulnerability to degeneration.