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MRes - Do cln3 mutant zebrafish recapitulate Batten disease, a childhood neurodegenerative disease?

Supervisors:  and Dr Valentina Marchica 

Department: Comparative Biomedical Sciences  

Project Details

The zebrafish is a prominent model to study inherited diseases. Mutations in CLN3 cause approximately half the cases of a group of severe recessively inherited neurodegenerative disorders affecting children1, the neuronal ceroid lipofuscinoses (NCL) or Batten disease. These are life-limiting monogenic recessive disorders that affect lysosomal homeostasis, with increased accumulation of autofluorescent lipofuscin that normally occurs with age2. Those affected by classic juvenile CLN3 disease (~45 currently in the UK, estimated >700 new cases diagnosed annually world-wide) suffer from rapid visual failure from 5 yrs3, followed by seizures and a progressive cognitive and psychomotor decline, with death by the fourth decade. Neurodegenerative diseases affecting children and young adults represent a significant unmet clinical need and are a health and socioeconomic burden for families and society. We have generated cln3 mutant zebrafish and also published antisense morpholino models (morphants) of CLN3 disease4 to provide proof-of-concept for our hypothesis that zebrafish with mutations in cln3 model human CLN3 disease.  

We also have data showing that three compounds show promise as treatments. We hypothesise that these compounds will reduce zebrafish cln3 mutant phenotypes, providing evidence for their potential clinical translation.  

Objectives: 

This project will focus on one zebrafish cln3 mutant and one compound: 

  1. To confirm the mutation at the level of the genomic and mRNA sequences (if not already performed) 
  2. To use established assays to characterise the embryo larval phenotype by examining clinical correlates including motor function (locomotion), brain activity (electroencephalography), visual function (electroretinography and optokinetic response) 
  3. To ascertain if the chosen compound reduces at least one of the phenotypes.  

Zebrafish at 24 hours post-fertilisation 

References

  1. Mole SE, et al., eds. The neuronal ceroid lipofusinoses (Batten disease). 2nd ed. Contemporary Neurology 2011, Oxford University Press: Oxford. 444.

  2. Warrier V, et al., Biochim Biophys Acta, 2013.

  3. Wright GA, et al., Ophthalmol Retina, 2020.

  4. Wager K, et al., PLoS One, 2016. 11: e0157365.  

Requirements

Essential:

  • Must meet our standard MRes entry requirements.
  • No need to be a vet
  • Willingness to work with zebrafish animal model (embryos up to 5 days post-fertilisation).
  • Strong motivation and commitment to learning. 

Desirable:

  • Previous lab experience.
  • Experience using zebrafish.  

This can be taken full-time or part-time (12months FTE) project commencing in October 2024, based at RVC's Camden campus. 

The animal model used is the zebrafish embryo (up to 5 days post-fertilisation), therefore no °ÄÃÅÁùºÏ²Ê¹æÂÉÂÛ̳ Office personal licence is required for this project. Any regulated procedures would be performed by the supervisors. However, there may be the opportunity to acquire a °ÄÃÅÁùºÏ²Ê¹æÂÉÂÛ̳ Office Personal License. 

Funding

Partially funded: The lab will be covering the project costs, with the MRes student expected to meet the course fees and their living expenses. 

International applicants are welcome to apply but must be able to fund the difference between "°ÄÃÅÁùºÏ²Ê¹æÂÉÂÛ̳" and "Overseas" tuition fees. Please note that EU/EEA and Swiss national students may no longer be eligible for the “°ÄÃÅÁùºÏ²Ê¹æÂÉÂÛ̳” rate of tuition fees, dependent on personal circumstances (including immigration status and residence history in the UK) and UK government rules which are currently being developed. For up-to-date information on fees for EU/EEA and Swiss national students following Brexit please see our fees and funding p²¹²µ±ð.&²Ô²ú²õ±è;

How to Apply

For more information on the application process and English Language requirements see How to Apply.

Deadline: 1pm UK time, Friday 5th April

We welcome informal enquiries - these should be directed to Dr. Claire Russel (crussel@rvc.ac.uk)

Interview date and location: TBC

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