Batten disease is a group of inherited neurodegenerative diseases that affects children, causing blindness, seizures, and motor and cognitive decline, and is the most common form of dementia in children. Our recent publication(1) using the yeast model S. pombe showed that the mutation causing nearly half of all types of Batten disease, which is a 1kb deletion in the CLN3 gene, is likely to cause both a loss and a change of function of the CLN3 protein. Gene therapy is a great hope for treating Batten disease, but our data suggests that adding back normal protein may not correct all aspects of the disease for CLN3 disease patients with the 1kb deletion mutation.
This MRC grant aims to identify all the transcripts produced by the 1kb deletion in tissues from Batten disease patients and then replicate these in yeast and zebrafish to produce accurate genetic models of Batten disease. This zebrafish model of CLN3 disease could then be used to find and test other, novel therapeutic approaches. This builds on our previous success in making a zebrafish knockout model of CLN3 disease(2).
The grant is led by Prof. Sara Mole, Professor of Molecular Cell Biology at UCL. Dr. Claire Russell, Senior Lecturer in Comparative Biomedical Sciences at the RVC is the Co-Investigator leading the zebrafish research, with collaborative support from Prof Jason Rihel (UCL) and Dr Anselm Zdebik (UCL). Further Co-Investigators are UCL Associate Professor of Paediatric Metabolic Metabolism Philippa Mills and UCL Professor of Clinical Genetics Mina Ryten. Dr Chris Minnis, former RVC and LIDo DTP PhD student supervised by Claire Russell and Sara Mole, is the Researcher-Co-Investigator.
(1)Minnis CJ, Townsend S, Petschnigg J, Tinelli E, Bähler J, Russell C, Mole SE. Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease. Sci Rep. 2021 Mar 18;11(1):6332. doi: 10.1038/s41598-021-85471-4. Erratum in: Sci Rep. 2021 Jul 5;11(1):14198. PMID: 33737578; PMCID: PMC7973434.
(2)Wager K, Zdebik AA, Fu S, Cooper JD, Harvey RJ, Russell C. Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease). PLoS One. 2016 Jun 21;11(6):e0157365. doi: 10.1371/journal.pone.0157365. PMID: 27327661; PMCID: PMC4915684.