Glial metabolic states in human sporadic amyotrophic lateral sclerosis uncovered by spatial single-cell proteomics.

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Abstract
Sporadic amyotrophic lateral sclerosis (ALS) is characterized by selective motor neuron vulnerability accompanied by prominent glial responses, yet their molecular heterogeneity and spatial organization in the human central nervous system and spinal cord remain incompletely defined. Here, we delineate ALS-associated glial states in situ by spatially resolved, single-cell proteomic profiling of postmortem human sporadic ALS and non-neurological control tissues across the motor cortex, spinal cord, and cerebellum. We identify subpopulations of astrocytes and microglia co-expressing both canonical ALS markers together with newly implicated ALS-associated proteins, including phosphorylated TDP-43, UBQLN2, TREM2, IL6ST, and glutaminase (GLS). These glial states are consistent with transcriptomic signatures characterized by TP53 and GLS upregulation, indicating convergence on senescence stress- and glutamine metabolism-related pathways. Notably, p53–GLS-associated profiles are selectively enriched in anatomically vulnerable regions in ALS, supporting region-specific glial metabolic alterations in human disease. Together, these findings provide insight into the metabolic alterations in ALS-affected human tissue and highlight the relevance of spatial context in shaping glial responses to neurodegeneration.

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