Editors' ChoiceImmunology

Impaired phagocytosis in fragile X

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Science Signaling  04 Apr 2017:
Vol. 10, Issue 473, eaan3520
DOI: 10.1126/scisignal.aan3520

Defects in phagocytosis underlie both neurological and immunological symptoms in a fly model of fragile X syndrome.

Autism spectrum disorders are epidemiologically associated with diverse immune symptoms. Fragile X syndrome is a monogenic disorder that results in both autism and other intellectual symptoms, and also in increased proinflammatory cytokine production and gut inflammation. The fragile X syndrome mutation results in suppression of the FMR1 gene, which encodes FMR1, an mRNA-binding protein present throughout the body but particularly enriched in neurons. O’Connor et al. found that in Drosophila melanogaster, FMR1 was required in the immune system for hemocyte phagocytosis of infectious bacteria and also in the brain for axonal pruning by phagocytic glia. Fmr1 mutant flies, which are deficient in FMR1 and have neurological deficits in memory and behavior, were exposed to several bacterial pathogens. Although Streptococcus pneumoniae and Serratia marcescens proliferated in and killed mutant flies more rapidly than wild-type flies, the expression of genes encoding antimicrobial peptides in response to infection did not differ between wild-type and mutant flies. The absence of FMR1 reduced engulfment of bacteria by hemocytes, a defect that also occurred after hemocyte-specific RNAi knockdown of Fmr1 and that was rescued by Fmr1 complementation. To determine the role that FMR1-mediated phagocytosis played in the brain, the authors severed axons of olfactory receptor neurons, a procedure that typically triggers phagocytosis by ensheathing glia to clear the cellular debris. Fmr1 mutant flies failed to clear severed neurons. Furthermore, during embryonic development, these flies also exhibited delays in axonal pruning in the mushroom body, a brain structure involved in learning and memory. Thus, the conserved role of FMR1 in regulating phagocytosis may be responsible for its effects on both neurological and immune function in fragile X syndrome. If this mechanism is conserved in human patients with other types of autism spectrum disorders, the authors suggest that phagocytosis could be used as a biomarker for these disorders at a young age.

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