This study examines how the C9orf72 gene mutation affects the immune response in the central nervous system of patients with amyotrophic lateral sclerosis (ALS). By comparing genetic and sporadic forms of the disease, researchers discovered that the C9orf72 mutation causes haploinsufficiency, which prevents microglia from transitioning into necessary reactive and protective states. Unlike sporadic ALS, where these immune cells successfully activate, mutated microglia show significant defects in endolysosomal pathways and waste degradation. The research further indicates that astrocytes also exhibit a diminished response in patients carrying the mutation, likely due to failing communication between different cell types. These findings were validated through single-nuclei RNA sequencing and human microglia xenograft models, highlighting that inherited and sporadic ALS involve distinct cellular mechanisms. Ultimately, the data suggests that personalized treatment strategies are essential because the underlying molecular pathology varies significantly between patient groups.

References:

• Masrori P, Bijnens B, Fumagalli L, et al. C9orf72 hexanucleotide repeat expansions impair microglial response in ALS[J]. Nature Neuroscience, 2025: 1-14.