Neurochondrin: a potential therapeutic target for motor neurone diseases?

Spinal Muscular Atrophy (SMA) is a devastating inherited motor neurone disease. It is the leading genetic cause of infant mortality and, in its severest form, results in life expectancy of less than two years. SMA is caused by lowered levels of the survival motor neurone (SMN) protein, but it is not understood how the deficiency in SMN, a multi-functional RNA binding protein essential in all cells, causes the symptoms which preferentially affect motor neurones. Newly licenced treatments for SMA that directly increase SMN expression are unlikely to be suitable for all patients and are extremely expensive, making the search for additional treatments to be used in combination with, or in place of, existing treatments vital (Groen et al, 2018). The development of these additional treatments is hampered by a lack of knowledge concerning the fundamental cellular functions of SMN. We recently identified the essential neural protein, neurochondrin (NCDN) as a potential therapeutic target for SMA (Thompson et al, 2018). We have shown that NCDN interacts with SMN in cells and intact tissues, is up-regulated in the spinal cords of SMA model mice and that its expression levels can affect the sub-cellular distribution of SMN, which is key to correct SMN function. We next need to determine whether modulating NCDN can improve the phenotype in a whole animal, zebrafish, model of SMA and develop a suitable screening platform for drugs that can alter NCDN expression using CRISPR technology. Using a non-SMN target for therapy development increases the possibility that therapies developed could also be useful for other forms of motor neurone disease, as molecular overlaps between different conditions are increasingly apparent.

This PhD project, in collaboration with Prof. Catherina Becker, University of Edinburgh, will combine cell biology, modelling of SMA in Zebrafish (Tsarouchas et al, 2018) and advanced microscopy approaches to investigate the potential of NCDN as a therapeutic target for SMA. The project will also investigate the fundamental cellular functions of NCDN, which are not yet clear, providing the potential to expand the work further into models of other types of motor neurone disease. Training will be given in all of these areas and the University of St Andrews also runs a world-class programme of training workshops and activities designed specifically for research postgraduate students.

Informal enquiries are strongly encouraged and should be made by email to Dr Judith Sleeman ([Email Address Removed]).