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  Investigating the role of SOD1 in sporadic Motor Neuron Disease patients using structural proteomics

   School of Biosciences

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  Dr M Collins, Dr Laura Ferraiuolo  Applications accepted all year round  Self-Funded PhD Students Only

About the Project


Motor Neuron Disease/Amyotrophic lateral sclerosis (ALS) is a complex neurological disorder characterised by the progressive degeneration of motor neurons that is thought to be caused by mitochondrial dysfunction leading to oxidative stress and neuroinflammation. SOD1 (Superoxide dismutase 1) was the first familial genetic risk factor identified for ALS, and over 200 mutations in SOD1 have been identified, accounting for 20% of familial ALS. Neurodegeneration in these patients is thought to be caused by the gain of function of toxic misfolded SOD1 mediated by mutations that disrupt metal ion binding, formation of disulphide bonds and dimerisation.

A recent phase 3 trial of an antisense oligonucleotide (Tofersen) targeting SOD1 in patients with SOD1 ALS showed a reduction of SOD1 in patient CSF that was associated with an improvement in motor function. This is the first trial that has reported such an improvement and is a very promising therapeutic strategy for SOD1 ALS. However, the majority of ALS patients are sporadic (sALS), and as such, a genetically targeted therapeutic strategy is not possible. However, there is evidence that SOD1 function in sALS is important. Secretomes from SOD1 ALS patient-derived astrocytes, when applied to healthy control cells, cause toxicity. Knockdown of SOD1 in these cells reduces this secretome-mediated toxicity. Furthermore, astrocytes from sALS patients show clear aggregates of misfolded SOD1, indicating that non-genetic causes of SOD1 dysfunction in sALS are important.


• Investigate structural changes of SOD1 protein in fibroblasts reprogrammed to astrocytes from SOD1-ALS and sALS patients versus healthy controls.

• Identify which of these structural changes are also present in CSF from the same patients used to generate reprogrammed astrocytes.

• Assess whether structural differences in SOD1 CSF can be used to identify which sALS cases might benefit from therapeutic targeting of SOD1.

Experimental Approach

This project will exploit a unique resource of CSF samples and reprogrammed astrocytes from the same cohort of sALS patients. To assess structural changes in SOD1 in these samples, we will use immunopurification of SOD1 coupled to covalent protein painting and quantitative proteomics. In this strategy, the conformation of a protein is inferred by the relative accessibility of protein residues to chemical labelling. The abundance of labelled residues is then determined by quantitative mass spectrometry of digested proteins. In CSF samples, a global strategy to assess structural changes in all proteins (including SOD1) will be used to provide an unbiased assay of protein conformation changes in sALS. The project will also use immunofluorescence microscopy to assess SOD1 localisation, assays to measure the extent of SOD1 bound to metal ions, as well as assays of SOD1 activity and glutathione oxidation in patient-derived astrocytes.

Biological Sciences (4) Medicine (26)

Funding Notes

This position is for self-funded or externally funded students only.
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link:
All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.


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