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Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration
Ziyang Zhang1,2, Lynn van Olst1,2, Francesco Alessandrini2
1Abrams Research Center on Neurogenomics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Nature Neuroscience
|May 14, 2026
Summary
This study reveals immune system changes in amyotrophic lateral sclerosis (ALS), linking peripheral and central immune alterations to disease subtypes and progression. Findings suggest targeted immunomodulation may be a future therapeutic strategy for ALS patients.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration.
- Neuroinflammation is a key feature of ALS, but its molecular links to motor neuron pathology are unclear.
Purpose of the Study:
- To investigate shared and distinct immune dynamics in sporadic ALS and C9orf72-associated ALS.
- To identify molecular programs connecting immune responses to motor neuron degeneration.
Main Methods:
- Integrated analysis of single-cell RNA sequencing, bulk RNA sequencing, and spatial proteogenomics.
- Characterization of immune cells in peripheral blood and spinal cord tissues from ALS patients.
Main Results:
- Identified broad immune remodeling in C9orf72 ALS.
- Revealed ALS subtype-specific and progression-associated differences in monocyte and CD8 T cell responses.
- Spatial mapping showed complement activation and myeloid states at sites of motor neuron loss and TDP-43 pathology.
Conclusions:
- Connected peripheral and central immune alterations to ALS heterogeneity.
- Highlighted stratified immunomodulation as a potential therapeutic strategy for ALS.