RESUMO
The contribution of microglia in neurological disorders is emerging as a leading disease driver rather than a consequence of pathology. RNAseT2-deficient leukoencephalopathy is a severe childhood white matter disorder affecting patients in their first year of life and mimicking a cytomegalovirus brain infection. The early onset and resemblance of the symptoms to a viral infection suggest an inflammatory and embryonic origin of the pathology. There are no treatments available for this disease as our understanding of the cellular drivers of the pathology are still unknown. In this study, using a zebrafish mutant for the orthologous rnaset2 gene, we have identified an inflammatory signature in early development and an antiviral immune response in mature adult brains. Using the optical transparency and the ex utero development of the zebrafish larvae we studied immune cell behavior during brain development and identified abnormal microglia as an early marker of pathology. Live imaging and electron microscopy identified that mutant microglia displayed an engorged morphology and were filled with undigested apoptotic cells and undigested substrate. Using microglia-specific depletion and rescue experiments, we identified microglia as drivers of this embryonic phenotype and potential key cellular player in the pathology of RNAseT2-deficient leukoencephalopathy. Our zebrafish model also presented with reduced survival and locomotor defects, therefore recapitulating many aspects of the human disease. Our study therefore placed our rnaset2 mutant at the forefront of leukodystrophy preclinical models and highlighted tissue-specific approaches as future therapeutic avenues.
Assuntos
Apoptose/fisiologia , Encéfalo/metabolismo , Leucoencefalopatias/patologia , Microglia/metabolismo , Animais , Leucoencefalopatias/metabolismo , Mutação/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fenótipo , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.