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bioRxiv · 10.1101/2023.12.04.569924

Macrophage transplantation rescues RNASET2-deficient leukodystrophy by replacing deficient microglia in a zebrafish model

Rutherford, H. A.·Candeias, D.·Duncan, C. J.·Renshaw, S. A.·Hamilton, N.
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Abstract

RNaseT2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there remain no treatments for this disorder, with little understanding of cellular mechanisms of pathogenesis. Recent research using the rnaset2 mutant zebrafish model has suggested that microglia - brain-resident phagocytes - may be the drivers of neuroinflammation in this disorder, due to their failure to digest apoptotic debris during early development. As such, the current study aimed to develop a strategy for microglial replacement and test the effects of this intervention on rnaset2 mutant zebrafish pathology. We developed a strategy for microglial replacement through transplantation of adult whole kidney marrow-derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting adoption of a microglial phenotype. Tissue clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescuing overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response, and particularly the antiviral response, in rnaset2-deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioural rescue - restoring rnaset2 mutant motor activity to wild type levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology in rnaset2 mutants, and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNaseT2-deficient leukodystrophy.

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Rutherford, H. A., Candeias, D., Duncan, C. J., Renshaw, S. A., Hamilton, N.. 2023-12-05. Macrophage transplantation rescues RNASET2-deficient leukodystrophy by replacing deficient microglia in a zebrafish model. https://doi.org/10.1101/2023.12.04.569924

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