Dementia causes enormous personal hardship and costs the UK ~£23 billion every year. The second most common form is Frontotemporal lobar degeneration (FTLD). About 40% of FTLD cases have genetic causes, with >8% involving abnormal aggregate-forming GA, GR, PR, GP and AP dipeptide repeat proteins (DPRs).
This project will gain new understanding of this type of FTLD by unravelling neurodegenerative pathomechanisms of DPRs through using interdisciplinary approaches. We will focus on the hypothesis that toxicity is caused by DPR structure, comparable to amyloid plaques in Alzheimer’s disease. The project will capitalise on the complementary expertises of the three supervisors. The detailed aims and outcomes are:
(1) To generate purified DPRs and perform biochemical and biophysical analyses, in order to understand the reasons for their toxicity and identify useful therapeutic strategies which will benefit patients and their families.
(2) To generate transgenic Drosophila fly stocks to obtain primary neurons expressing the four DPRs. We will use powerful fly genetics and well established cell biological approaches to identify the neuronal death pathway (apoptosis, necrosis, autophagy), to then block cell death and carry out a detailed analysis of the DRP pathomechanisms upstream.
(3) There is substantial proof-of-principle for the use and translational potential of Drosophila neurons. To validate identified DPR pathomechanisms in mammalian contexts, we will carry out complementary experiments using well established DPR models in SH-SY5Y cells and inducible neuronal cell lines.
The training will therefore provide plenty of opportunities to acquire skills in a wide range of techniques within the areas of genetics, cell biology, and biochemistry, supervised by three specialists in these areas: Stuart Pickering Brown, Andreas Prokop and Andrew Doig. For more details, please contact Stuart via email: SPB@manchester.ac.uk.