Motor neuron disease (MND) is an adult-onset disorder involving the death of motor neurons that interact with skeletal and bulbar muscles. Age is a significant risk factor, with patients surviving typically no more than 2-3 years after symptom onset. Due to the complex, multi-factorial heterogeneity of the disease, there is currently no cure. Metabolic dysfunction plays a key role in disease progression and clinical evidence supports a negative impact of dysfunctional energy metabolism on MND disease progression rates. Using a phenotypic metabolic screen, we have identified a novel defect in nucleoside metabolism in inducible neuronal progenitor cell (iNPC) models of MND, potentially due to a loss of a key enzyme involved in this transition. Enzymes levels were found to be reduced in multiple cell models of MND. Furthermore, in preliminary data using post mortem motor cortex from patients with MND, enzyme expression levels correlated with age of death in patients. Therefore, the overall aim of this project is to investigate the role of the enzyme in motor neuron disease.
We will investigate this by:
- Building on our preliminary data in patient brain tissue by investigating the levels of the enzyme in larger numbers of both motor cortex and cerebellum post-mortem samples. We will assess whether levels correlate with age of death, age of onset, disease progression rates and post mortem interval time in both familial and sporadic patients compared to controls. This will assess whether enzyme levels are altered in healthy subjects over time and how neurodegeneration alters these expression levels.
- Ascertaining whether enzyme levels are altered with age in the context of a vertebrate whole organism. We will measure enzyme levels in zebrafish expressing a transgenic mutation that causes MND. Zebrafish are a well-established MND model and will allow us to also compare muscle and brain levels of the enzyme with age. We will measure levels at multiple age time points including prior to symptom onset, at symptom onset and at death and compare these levels to healthy zebrafish at the same age.
- Investigating whether restoration of enzyme levels in iNPC derived human astrocytes rescues motor neurons in co-culture and reduces the disease pathogenic mechanisms we observe in these models including blockages of autophagy, cytoplasmic aggregation of nuclear proteins and impairment in the DNA repair mechanisms. We will achieve this by transfecting the enzyme into these cells and engineer GFP into the vector to check for transfection levels by immunofluorescence.
This work will be performed in the Sheffield Institute for Translational Neuroscience at the University of Sheffield with supervisors within the department who are experts on metabolic profiling and the use of zebrafish models to study neurodegenerative disease such as MND.
The Faculty Scholarships for Medicine, Dentistry & Health cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.
Candidates should possess a 2:1 minimum or 2:2 with +1 year neuroscience research experience