Project title: Elucidating the mechanisms of pathology in neurodevelopmental white matter diseases

Our research interest is to dissect the mechanism of auto-inflammatory neurological disorders using zebrafish as an animal model.

Cystic leukoencephalopathy without megalencephaly is a rare leukodystrophy that arises in infancy and is characterised by white matter lesions with mental and motor impairments. The disease is caused by mutations in the gene encoding ribonuclease T2 (RNAseT2) and clinically resembles congenital cytomegalovirus (CMV) infection (Henneke et al, 2009), sharing features with the auto-inflammatory Aicardie-Goutières Syndrome. There is nothing known about the pathological mechanisms and there is no treatment available for this rare and severe childhood leukodystrophy.

I have previously published the first genetic model to study RNAseT2 deficiency using a loss of function zebrafish mutant for the orthologous rnaset2 gene (Haud et al, PNAS, 2011). MRI scans from adult zebrafish rnaset2 mutants revealed white matter lesions similar to those seen in patients, with abnormal locomotor behaviour and increased inflammation. We have now identified the immune cells of the brain, the microglia, as cellular drivers of the disease (Hamilton et al, BioRxiv 2019).

The student will be working towards elucidating the mechanism of pathology to further our understanding of the disease. This will contribute to the development of therapy to target microglia and reduce brain inflammation.