Understanding alpha-synuclein processing in human microglia and the immunoproteasome
Supervisors
Dr Katrina Räty, Lancaster University
Professor Paula da Fonseca, University of Glasgow
Dr Edward Parkin, Lancaster University
Summary
Alpha-synuclein (αSyn) is a small protein predominantly expressed in presynaptic nerve terminals that can form fibrils closely associated to neurodegenerative disorders and are a hallmark of Parkinson’s disease. However, the endogenous functional mechanisms of αSyn in healthy individuals is still not fully understood. The project will focus on the study of αSyn and its interaction with and processing by human microglia. Microglia are the immune cells of the brain, and one of their functions is to take up and clear away excess extracellular proteins. We have previously shown that microglia can uptake αSyn fibrils and break them into small fragments. This may be a protective mechanism and needs to be further explored.
The aim of the project is to characterise how αSyn interacts and is processed by microglia to address: 1) where does the αSyn protein localize in the microglia; 2) what is the structure and any posttranslational modifications of the small αSyn fragment; 3) are there any downstream effects in the microglia triggered by the intake of αSyn? For this, we will employ cell, molecular, and structural biology techniques. Therefore, the student can expect to master methods in differentiation of human microglia, protein characterization and quantification, biophysical/structural biology (e.g. cryo-EM).