Lysosomal storage disorders and Parkinson’s disease; related mechanisms of pathogenesis and identification of novel therapeutic targets
PhD Research
Funding:
The full studentship (fees and stipend) is available to UK or EU students who have been resident in the UK for at least three years. Other EU participants may receive a fees only award.
Applicants capable of self-funding (UK, EU and international) are also welcome to apply.
Project description:
Primary Supervisor: Dr Emry Lloyd-Evans
Secondary Supervisor: Prof Vladimir Buchman
The lysosomal storage diseases (LSDs) are a group of rare inherited metabolic disorders characterized by storage of multiple metabolites within lysosomes leading to cellular dysfunction and ultimately death. Research into the LSDs has provided insight into the mechanisms of other diseases including tuberculosis and cystic fibrosis.
Recently, Parkinson’s disease (PD) has been linked to Gaucher disease where loss of lysosomal glucocerebrosidase (GBA1) leads to accumulation of the glycosphingolipid glucosylceramide and ultimately neurodegeneration. Interestingly, all Gaucher patients have PD and mutations in the GBA1 gene is now a confirmed risk factor for PD (~10% of non-Ashkenazi Jewish and ~20% of Ashkenazi Jewish PD patients are predicted to carry GBA1 mutations). How GBA1 dysfunction contributes to PD remains unknown. We study a group of LSDs (Niemann-Pick type C) and related disorders all of which have confirmed Parkinsonism where the GBA1 enzyme is functional but is mislocalised leading to accumulation of the lipid substrate in lysosomes.
The student will study the role of GBA1 in PD pathogenesis utilizing LSD and PD cellular, pharmacological and transgenic rodent model systems to determine how enzyme or substrate dysfunction leads to PD. These studies include the effects of lysosomal GBA1 and glucosylceramide in: i) modifying the synucleins and Parkin (expression, localisation and post-translational modification), ii) altering endocytosis and receptor recycling and, iii) as we have reported in Gaucher disease, altering intracellular calcium signaling leading to potential endoplasmic reticulum protein mis-folding and stress.
These studies will help identify novel mechanisms of pathogenesis in PD that can be targeted therapeutically. This project is suitable for a biological sciences graduate.