Plymouth University - Neurotropic signalling Professor Robert Fern & Dr Konstantin Glebov Supervisors - Neurotrophic signalling to protect neurones in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) (PhD Studentship) Summary The glia cell line-derived neurotrophic factor (GDNF) and its receptor Ret is being studied to understand how they interact with alpha-synuclein. The role of alpha-synuclein in the inherent cellular processes of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) will be investigated. studied In addition, the possible attenuation of the degeneration process by GDNF/Ret signalling will be analysed. All of this should help inform the use of GDNF/Ret activation as a therapeutic treatment for PD and DLB. What do we already know? Glia cell line-derived neurotrophic factor (GDNF) is currently being tested in clinical trials to prevent degeneration of dopaminergic neurones in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Ret is a receptor for GDNF which has been found to increase the survival of neurones in the brain. This PhD studentship looks to characterise fully the levels of Ret in cells dying in PD pateints which have accumulated alpha-synuclein. What is this project trying to find out? Aim 1: To assess the amount of Ret protein in PD and DLB brains during disease progression. To correlate the amount of Ret and alpha-synuclein in brain cells in correlation with alpha-synuclein load. Aim 2: To define the cell signalling pathways and cellular processes affected by GDNF / Ret signalling in brain neurones. The cell signalling pathways which are important for neurone survival will be focussed on. Aim 3: The progression of neurodegeneration into other brain regions will be explored over time. How will they do this? Aim 1: Brain tissue from multiple brain banks around Europe (including BRACE funded Bristol Brain Bank) will be used in this study. The amounts of Ret protein in samples will be monitored at 6 different stages of PD and DLB disease progression. In addition, the levels of alpha-synuclein in samples will be measured so a correlation between Ret and alpha-synuclein can be investigated. Aim 2: A series of laboratory techniques will be used to understand how the biological processes in the cell are affected by Ret/GDNF and alpha synuclein. This will be achieved by analysis of neurones in the presence and absence of alpha-synuclein at different stages of disease progression. Aim 3: The presence of alpha-synuclein, Ret and other markers of PD and DLB in the brain will be monitored at different stages of disease progression. This will allow the determination of the best time point for GDNF treatment during disease progression. Why is this important? This project will shed light on important open questions regarding the ongoing clinical trials using GDNF in PD and DLB patients. GDNF looks like a promising treatment for the neurodegeneration caused by PD and DLB but has so far been unsuccessful. Unlocking the potential of this treatment is of vital importance for PD and DLB patients worldwide. Glossary Alpha-synuclein - A protein which accumulates in cells leading to protein aggregates associated with Parkinson’s disease and dementia with Lewy bodies.Dopaminagenic system – The set of neurones in the brain which synthesise and release the neurotransmitter domamine.Neurotrophic Factor – A class of peptites and small proteins which support the survival, growth and differentiation of neurones. Therapeutic treatment – Related to the treatment of a disease.