An emergent disease-associated motor neuron state precedes cell death in ALS.

Vulnerable alpha motor neurons in ALS develop a conserved, disease-associated state marked by distinct molecular changes and transcription factor networks, occurring before cell death.

• Why it matters: Understanding the molecular transitions leading to motor neuron degeneration is crucial for developing targeted therapies for ALS, yet the specific early cell states remain unclear.
• What they did: The study used longitudinal single-nucleus transcriptomics, chromatin accessibility profiling, and spatial transcriptomics on the SOD1-G93A mouse model, identifying a unique "disease-associated motor neuron" (DM) state.
• The result: Findings reveal that DMs are conserved in human ALS, linked to genetic risk variants, and their active regulatory networks offer potential targets for early intervention in ALS progression.