Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations.

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) that innervate skeletal muscles. However, certain MN groups including ocular MNs, are relatively resilient. To reveal key drivers of resilience versus vulnerability in ALS, we investigate the transcriptional dynamics of four distinct MN populations in SOD1G93A ALS mice using LCM-seq and single-molecule fluorescent in situ hybridization. We find that resilient ocular MNs regulate few genes in response to disease. Instead, they exhibit high baseline gene expression of neuroprotective factors, including,,, and, some of which vulnerable MNs upregulate during disease. Vulnerable MN groups upregulate both detrimental and regenerative responses to ALS and share pathway activation, indicating that breakdown occurs through similar mechanisms across vulnerable neurons, albeit with distinct timing. Meta-analysis across four rodent mutantMN transcriptome data sets identify a shared vulnerability code of 39 genes, including,,, and, involved in apoptosis, as well as a proregenerative and antiapoptotic signature consisting of,,,,,,, andMachine learning using genes upregulated in SOD1G93A spinal MN predicts disease in human stem cell-derivedMNs and shows that dysregulation of,, andis a strong disease predictor across species andmutations. Our study reveals MN population-specific gene expression and temporal disease-induced regulation that together provide a basis to explain ALS selective vulnerability and resilience and that can be used to predict disease.