Neurology · Pediatrics · 2 h ago
Mouse study links microglial lysosomal dysfunction to fragile X features
A study in mice implicates microglial FMRP and lysosomal function in fragile X syndrome-related phenotypes. Increasing progranulin expression rescued audiogenic seizures and parvalbumin-neuron loss in a mouse model; the findings have not established a treatment approach in people.
- Microglial Fmr1 deletion reproduced selected fragile X mouse phenotypes.
- FMRP deficiency was linked to impaired lysosomal function.
- Progranulin overexpression rescued two phenotypes in mice.
- The findings do not establish a human treatment.
Fragile X syndrome results from silencing of FMR1, which encodes FMRP. In this preclinical study, researchers selectively deleted Fmr1 in mouse microglia and examined disease-related features, using single-nucleus RNA sequencing and RNA immunoprecipitation to investigate molecular mechanisms. The abstract does not report the number of animals studied.
Mice with microglia-specific Fmr1 deletion developed audiogenic seizures and loss of parvalbumin-expressing neurons, phenotypes also seen in Fmr1-deficient mice. The researchers found that FMRP binds several lysosomal messenger RNAs and supports lysosomal protein expression. FMRP deficiency impaired microglial lysosomal function and reduced progranulin, a protein encoded by Grn. Progranulin overexpression rescued seizures and parvalbumin-neuron loss in Fmr1-deficient mice.
The results identify a possible microglial contribution to fragile X pathogenesis and a candidate mechanism for further study. They are based on mouse experiments and do not show that progranulin treatment is effective or safe in people with fragile X syndrome; clinical implications remain uncertain.
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Molecular Psychiatry: A microglial basis for fragile X syndrome via impairment of FMRP-regulated lysosomal function ↗This is an automated AI-condensed summary that has not yet been reviewed by an editor. Always consult the full item at the original source.