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Targeting the DNA damage response in spinal muscular atrophy.

School of Health and Life Sciences

About the Project

Reference No: SHLS20040

Spinal muscular atrophy (SMA) is a neuromuscular disease that is the leading genetic cause of infant mortality in humans and it is caused by mutations in a single gene known as survival motor neuron 1, SMN1, resulting in loss of the SMN protein. There is currently no cure for SMA, although recent developments have led to the approval of two therapeutics that improve pathology in many patients. However, not all patients improve following treatment and it is now crucial to understand the exact biological cause(s) underlying this disease so that therapeutic interventions can be identified that can benefit the majority of, if not all, patients.

In our lab (https://ghunterhamilton.wixsite.com/researchprofile) we are undertaking a variety of projects to try and understand more fully the molecular mechanisms underlying SMA. Of particular interest we have recently published work showing that a gene called Uba1 is expressed at significantly lower levels in SMA tissues (Wishart et al, 2014). Uba1 protein is required for the cellular response to DNA damage (Moudry et al, 2012) and a recent study identified double-stranded DNA breaks in the genomes of SMA animal models (Jangi et al, 2017).

In this project, we aim to explore the link between reduced levels of Uba1 and DNA damage in more detail. We will develop a range of in vitro and in vivo models of SMA to confirm the link between loss of SMN and increased levels of DNA damage. Next, we will determine whether loss of Uba1 recapitulates the DNA damage phenotype using our optimised SMA models. Finally, we will explore whether two drugs known to be neuroprotective in models of neurodegeneration provide any therapeutic benefit to our SMA models (Tuxworth et al, 2019).

This project will enable the successful student to develop expertise in a variety of methods including cell culture, immunostaining, immunoblotting, quantitative PCR and microscopy.


Jangi et al (2017) PMID: 28270613
Moudry et al (2012) PMID: 22456334
Tuxworth et al (2019) https://academic.oup.com/braincomms/article/1/1/fcz005/5526876
Wishart et al (2014) PMID: 24590288

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