An emergent disease-associated motor neuron state precedes cell death in ALS
To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model.
Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component.
Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants.
Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.
HIGHLIGHTS
• Longitudinal multi-omic profiling of motor neurons in SOD1-ALS mice
• Vulnerable alpha motor neurons adopt a disease-associated motor neuron state (DM)
• Transcription factor networks govern motor neuron state transitions
• DM features are conserved in human ALS
Web | DOI | PDF | Cell | Open Access
Olivia Gautier; Jacob A Blum; Thao P Nguyen; Shaolong Cao; Sandy Klemm; Mai Yamakawa; Dann Huh; Jessica A Hurt; Nasa Sinnott-Armstrong; Yi Zeng; Chung-ha O Davis; Juliane Bombosch; Chang Liu; Lisa N Encarnacion; Kevin A Guttenplan; Derek Chen; Arwa Kathiria; Luke Zhao; Stephen Moore; Alex Meng; Kailee Ong; Don W Cleveland; John Ravits; Jessica E Rexach; William J Greenleaf; Aaron D Gitler
To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model.
Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component.
Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants.
Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.
HIGHLIGHTS
• Longitudinal multi-omic profiling of motor neurons in SOD1-ALS mice
• Vulnerable alpha motor neurons adopt a disease-associated motor neuron state (DM)
• Transcription factor networks govern motor neuron state transitions
• DM features are conserved in human ALS
Web | DOI | PDF | Cell | Open Access