Define the role of microglia in the pathology of leukodystrophies

Leukodystrophies are rare paediatric neurological disorders characterised by white matter lesions (WMLs), devastating psychomotor impairments and neuroinflammation.

Despite their severity, leukodystrophies have limited treatments and the mechanisms of pathogenesis are often unknown due to the lack of preclinical animal model available to study the disease. My aim is to develop effective therapies for these disorders.

I pioneered the use of zebrafish to model leukodystrophies using an archetypal disorder: Ribonuclease T2 (RNASET2)-deficient leukodystrophy which, in human, mimics a congenital cytomegalovirus brain infection, suggesting a role for RNASET2 in antiviral immunity.

My work using this zebrafish mutant characterised the disease as a lysosomal storage disorder, accumulating undigested RNA in the brain.

Using microglia-targeted approaches, including depletion, tissue-specific rescue and microglia replacement by macrophage transplantation, we demonstrated that microglia are drivers of the pathology during brain development.

Embryonic pathology, including neuroinflammation and locomotion defects, is rescued when microglia are replaced with healthy macrophages.

The objectives of this project are to 1) Validate the therapeutic effect of macrophage transplantation post brain development, by monitoring swimming behaviour, WMLs presence by MRI and survival analysis. 2) Identify the cellular and molecular changes before and after therapeutic intervention using single cell RNA sequencing (scRNAseq).

This will generate the first scRNAseq dataset of a leukodystrophy animal model to identify the molecular changes induced by transplanted cells and new functions of microglia in neuro-immune communication.

The identified pathways/genes could down the line be leveraged as novel drug target to manipulate microglia function in leukodystrophies.