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

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

doi:10.1016/j.cell.2026.05.047

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

Cell. 2026 Aug 6;189(16):5044-5064.e12. doi: 10.1016/j.cell.2026.05.047. Epub 2026 Jun 23.

Authors

Olivia Gautier¹, Jacob A Blum², Thao P Nguyen², Shaolong Cao³, Sandy Klemm², Mai Yamakawa⁴, Dann Huh³, Jessica A Hurt³, Nasa Sinnott-Armstrong⁵, Yi Zeng⁶, Chung-Ha O Davis⁷, Juliane Bombosch², Chang Liu², Lisa N Encarnacion², Kevin A Guttenplan⁸, Derek Chen², Arwa Kathiria², Luke Zhao², Stephen Moore⁹, Alex Meng¹⁰, Kailee Ong¹⁰, Don W Cleveland⁹, John Ravits¹⁰, Jessica E Rexach¹¹, William J Greenleaf¹², Aaron D Gitler¹³

Affiliations

¹ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: ogautier@stanford.edu.
² Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Research, Biogen Inc., Cambridge, MA 02142, USA.
⁴ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Herbold Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute, University of Washington, Seattle, WA 98195, USA.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Biohub - San Francisco, San Francisco, CA 94158, USA.
⁷ Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
⁸ Vollum Institute, Oregon Health and Sciences University, Portland, OR 97239, USA.
⁹ Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁰ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
¹¹ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Applied Physics, Stanford University, Stanford, CA 94305, USA; Biohub - San Francisco, San Francisco, CA 94158, USA.
¹³ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Biohub - San Francisco, San Francisco, CA 94158, USA; The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA 94305, USA. Electronic address: agitler@stanford.edu.

Abstract

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.

Keywords: ALS; cell states; microglial activation; motor neuron; neurodegeneration; selective vulnerability; snATAC-seq; snRNA-seq; spatial transcriptomics; spinal cord.

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Amyotrophic Lateral Sclerosis* / pathology
Animals
Cell Death
Disease Models, Animal
Female
Humans
Male
Mice
Mice, Transgenic
Motor Neurons* / metabolism
Motor Neurons* / pathology
Spinal Cord / metabolism
Spinal Cord / pathology
Superoxide Dismutase-1 / genetics
Superoxide Dismutase-1 / metabolism
Transcription Factors / metabolism
Transcriptome / genetics

Substances

Superoxide Dismutase-1
Transcription Factors

Abstract

MeSH terms

Substances

Grants and funding