The failure of microglia to digest developmental apoptotic cells contributes to the pathology of RNASET2‐deficient leukoencephalopathy
| Autor: | Marco Henneke, Stephen A. Renshaw, Noémie Hamilton, Jessica J. Petts, Thomas Weber, Mark J Dunning, Jutta Gärtner, Hannah M. Isles, Holly A. Rutherford |
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| Rok vydání: | 2020 |
| Předmět: |
leukodystrophy
Pathology medicine.medical_specialty microglia microglia depletion Apoptosis Disease Leukoencephalopathy 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Immune system Leukoencephalopathies medicine Animals RNaseT2 Zebrafish Research Articles 030304 developmental biology 0303 health sciences biology Microglia Leukodystrophy Brain Neurodegenerative Diseases Zebrafish Proteins zebrafish biology.organism_classification medicine.disease developmental apoptosis Phenotype Embryonic stem cell 3. Good health medicine.anatomical_structure Neurology Mutation lysosomal storage disorder 030217 neurology & neurosurgery Research Article |
| Zdroj: | Glia |
| ISSN: | 1098-1136 0894-1491 |
| Popis: | 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. Main Points Loss of rnaset2 results in inflammation and lysosomal‐deficient microglia failing to digest dying neurons.Targeting microglia restores embryonic microglial defects to clear neurodevelopmental apoptosis.Mutants have reduced survival and locomotor defects. |
| Databáze: | OpenAIRE |
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