PROTEASOME-AMYLOID · Linking aggregation of alpha-synuclein to proteasomal dysfunction; an investigation of the causes leading to Parkinson's disease

Parkinson’s disease (PD) is a severe neurodegenerative disease affecting more than 800000 people in Europe. Aggregation of the brain protein alpha-synuclein (aS) and its deposition into intracellular inclusions is a crucial event in the pathway leading to the onset of this tremendous disease. This process is triggered by alterations of the delicate homeostasis between production, aggregation and degradation of aS. aS aggregates are toxic to neurons and have been shown to impair proteasome, the cellular machinery which degrades misfolded/deleterious proteins. Little is known about the interplay between aS and proteasome. This lack of information currently represents one of the major limits to the development of new therapies for treatment of PD. The aim of this project is to carry out an unprecedented characterization of the interaction between aS and human proteasome and to investigate the effect that proteasome has on aS aggregation. By coupling computer predictions with cutting edge experimental methodologies such as NMR and single molecule measurements, we will characterize the regions of aS responsible for interacting with proteasome and the aggregated species responsible for impairment of proteasomal activity. Furthermore, the ability of proteasome to revert/inhibit aggregation of aS will be assessed studying aS aggregation in the presence of proteasome. The outcome of this research will provide missing building blocks to reach a complete knowledge of PD causes and will lead to the identification of new targets for molecular pharmacology, contributing to the development of new therapies for PD. The work will be undertaken in Prof. Dobson’s group, at the Department of Chemistry of the University of Cambridge (UK), one of the top research Institutes in Europe. The possibility to join this group and to master innovative techniques complementary to his background will allow the researcher to grow as a mature scientist able to perform multidisciplinary research.