Failure to clear developmental apoptosis contributes to the pathology of RNASET2-deficient leukoencephalopathy.
Hamilton, N.; Rutherford, H. A.; Isles, H. M.; Petts, J. J.; Henneke, M.; Gaertner, J.; Dunning, M.; Renshaw, S. A.
Show abstract
The contribution of microglia in neurological disorders is emerging as a leading 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 mimics a cytomegalovirus brain infection. The early onset and resemblance of the symptoms to an immune response suggest an inflammatory and embryonic origin of the pathology. In this study, we identify deficient microglia as an early marker of pathology. Using the ex utero development and the optical transparency of an rnaset2-deficient zebrafish model, we found that dysfunctional microglia fail to clear apoptotic neurons during brain development. This was associated with increased number of apoptotic cells and behavioural defects lasting into adulthood. This zebrafish model recapitulates all aspect of the human disease to be used as a robust preclinical model. Using microglia-specific depletion and rescue experiments, we identified microglia as potential drivers of the pathology and highlight tissue-specific approaches as future therapeutic avenues.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- A macrophage subpopulation promotes airineme-mediated intercellular communication in a Matrix Metalloproteinase-9-dependent manner 94%
- Piezo1-dependent regulation of pericyte proliferation by blood flow during brain vascular development 93%
- Silc1 long noncoding RNA is an immediate-early gene promoting efficient memory formation 93%
Similar papers in this journal
- CLN3 deficiency leads to neurological and metabolic perturbations during early development 94%
- Wound closure after brain injury relies on force generation by microglia in zebrafish 93%
- Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction in C9orf72 ALS/FTD in vivo models and patient iNeurons 93%
Similar papers in this journal
- Mosaic and non-mosaic pcdh19 mutation leads to neuronal hyperexcitability in zebrafish 96%
- TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43. 94%
- Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system 93%