We combine the transparency and the genetic tractability of the zebrafish to model rare neurological diseases, focusing on monogenic leukodystrophies. As a vertebrate and a non-mammalian model amenable to high-throughput assays, the zebrafish plugs the hole between in vitro modelling and expensive rodent models, therefore offering a non-mammalian in vivo model incorporating the 3Rs values in animal research (Replacement, Reduction and Refinement).
Our lab uses zebrafish across many projects with 2 main objectives:
We are currently working on 3 diseases:
-RNASET2-deficient leukodystrophy ( Previously funded by the European Leukodystrophy Association and the Jules Thorn Foundation, and currently funded by the MRC and Academy of Medical Sciences). We have created the first animal model for this disease suing ENU mutagenesis and CRISPR/Cas9 (Haud et al, 2011 PNAS). Using those mutants, we have identified the microglia as drivers of the pathology (Hamilton et al, 2020 Glia) allowing us to develop microglial replacement as a therapy (see below).
-SUPV3L1-deficient leukodystrophy-associated neurodevelopmental disorder (Funded by the White Rose, LEUKOLABS, and the Department of Biology- University of York). We have developed a zebrafish model using CRISPR/Cas9 and identified a severe mitochondrial defect in microglia associated with a increased antiviral immune response, matching what is found in patients (Green and Hamilton et al, 2024 Preprint). We are now dissecting the contribution of the antiviral immune response to the pathology using zebrafish, fly and iPSC-derived brain organoid models (in collaboration with Dr Poulter Leeds).
-Krabbe Disease (Previously funded by the Legacy of Angels/Rosenau Foundation with Prof Laura Feltri) or Globoid Leukodystrophy is a lysosomal storage disorder affecting children with devastating consequences. Krabbe Disease has an excellent mouse model mimicking the human disease, but there are still too many obscure areas in our understanding of the pathology: how do globoid cells form? How early does the pathology start? Is it myelin dependent? All those questions we hope to answer using live imaging of the developing zebrafish brain.
