Background: Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the two most common neurodegenerative conditions. Both of them are relentlessly progressive. There is therefore a desperate need to develop new drugs with the potential to slow down the disease progression in either disease. Mitochondrial dysfunction is well documented in PD, we have shown mitochondrial dysfunction can be measured in fibroblasts from patients with early onset familial PD (due to parkin mutations; Mortiboys et al, 2008), late onset familial PD (due to LRRK2 mutations; Mortiboys et al, 2010) and sporadic PD. We carried out a drug screen of 2000 compounds in parkin mutant patient fibroblasts which led to the identification of ursodeoxycholic acid (UDCA; Mortiboys et al, 2013). UDCA can rescue mitochondrial membrane potential and cellular ATP levels in both parkin mutant and LRRK2 mutant patient fibroblasts (Mortiboys et al, 2013, 2015). UDCA also acts to protect cells in a LRRK2 Drosophila model of PD (Mortiboys et al, 2015).
Aim: The project will elucidate the rescue abilities of a series of novel bile acids in models of neurodegenerative disease, primarily focused on PD and AD. By the end of this project, we are hoping to have identified a group of UDCA derivatives with substantially enhanced biological effect.
Workplan: The compounds will initially be tested in PD and AD patient derived fibroblasts using overall mitochondrial assays and toxicity assays; with structure function activity relationships characterised and subsequent compound libraries made for further screening. This will be an iterative process with the biological activity of the compounds providing further information to refine the chemical structures and retain maximal activity whilst achieving favourable drug properties. A selected group of compounds will be tested for mitochondrial recovery potential in neurons derived from PD and AD patient fibroblasts using induced neuronal progenitor (iNP) cell technology. The iNP cells can be differentiated into dopaminergic neurons for Parkinson’s Disease models. The detailed mechanism of action for the compounds will be investigated using in depth mitochondrial and cellular assays.
Outlook: The project will enable us to use the structure function activity relationship information we gain about the compounds in various patient derived models of common neurodegenerative diseases to progress our understanding of how these compounds work and their potential as therapeutic agents.
How to apply
Please complete a University Postgraduate Research Application form: http://www.shef.ac.uk/postgraduate/research/apply and attach at least two references to your application.
Please clearly state the prospective main supervisor in the respective box and select ‘Neuroscience’ as the department. Please include the project title in your supporting statement.
Deadline: Friday 19th February 2016
Supervisor: Dr Heather Mortiboys and Professor Oliver Bandmann
Enquiries: Please contact Dr Heather Mortiboys ([email protected]
) for further information in the first instance.