Vieira, MCD; (2015) Towards therapy for Batten disease. Doctoral thesis , UCL (University College London).

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Abstract

The gene underlying the classic neurodegenerative lysosomal storage disorder (LSD) juvenile neuronal ceroid lipofuscinosis (JNCL) in humans, CLN3, encodes a polytopic membrane spanning protein of unknown function. Several studies using simpler models have been performed in order to further understand this protein and its pathological mechanism. Schizosaccharomyces pombe provides an ideal model organism for the study of CLN3 function, due to its simplicity, genetic tractability and the presence of a single orthologue of CLN3 (Btn1p), which exhibits a functional profile comparable to its human counterpart. In this study, this model was used to explore the effect of different mutations in btn1 as well as phenotypes arising from complete deletion of the gene. Different btn1 mutations have different effects on the protein function, underlining different phenotypes and affecting the levels of expression of Btn1p. So far, there is no cure for JNCL and therefore it is of great importance to identify novel lead compounds that can be developed for disease therapy. To identify these compounds, a drug screen with btn1Δ cells based on their sensitivity to cyclosporine A, was developed. Positive hits from the screen were validated and tested for their ability to rescue other specific phenotypes also associated with the loss of btn1. The same hits were also tested in JNCL patient fibroblasts and in a zebrafish model of the disease. Promising results were obtained for three compounds: alloxazine, prochlorperazine dimaleate and E-64, with the latest being the one with the most potential for developing therapeutic tools. Yeast models for other LSDs (Chédiak Higashi Syndrome, Niemann-Pick disease type C2 and congenital CLN10 disease) were also characterised in terms of cellular phenotypes and the compounds described above were also tested in these models. Overlapping phenotypes were observed on all the yeast models, suggesting at least one common pathway between these LSDs.

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