Alpha-synuclein has been closely associated with Parkinson’s disease. Similar to other amyloidogenic proteins, such as Aβ42 or Tau protein, Alpha-Synuclein aggregates to form fibrils, found in every Parkinson patient. Currently it is unknown if these fibrils or smaller aggregates are the toxic species that lead to cell death, although the latter seem to make more sense. It has been suggested that amyloido- genic proteins associate with the membrane bilayer of a cell to form pores, thus disrupting the balance within a cell.
Alpha-synuclein is a special protein in the sense that under native conditions it has no stable secondary structure elements. Proteins with these characteristics are called intrinsically disordered and often play important roles in signal transduction in the cell, because their unstructuredness allows them bind with a large variety of binding partners.
In this project you will work on alpha-synuclein, using ion mobility mass spectro- metry to investigate how the conformation of alpha-synuclein changes upon binding a membrane bilayer or detergent micelle. Several reports have claimed that binding such a surface allows alpha-synuclein to obtain secondary structure, which is suggested to be the basis of aggregation for this protein. You will investigate the effect of several detergent micelles as well as nanodiscs (a combination of protein and lipids, which resembles the native membrane bilayer of a cell) on the conformation and aggregation dynamics of alpha-synuclein. You will strengthen your results by circular dichroism experiments, which can tell us about the secondary structure elements alpha-synuclein has, and possibly Raman optical activity. The obtained results, might give a better insight in how alpha-synuclein causes Parkinson’s disease.