Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome

Significance Genetic variation at the FMR1 locus confers risk for both the neurodevelopmental disorder fragile X syndrome and the neurodegenerative condition fragile X-associated tremor/ataxia syndrome. Although animal models have been critical in elucidating molecular mechanisms of cellular dysfunction in fragile X-related disorders, understanding how the human brain is directly impacted remains unresolved. We conducted a cell type–specific transcriptomic analysis of postmortem human brains from individuals with fragile X mutations and matched controls, sequencing over 120,000 nuclei from the frontal cortex and cerebellum. We find evidence for cell type–specific, disease-specific, and regional-specific patterns of transcriptional and FMR1 protein (FMRP) network perturbations, providing a foundation for therapeutic development directly derived from the human condition.