Humanized yeast models to study alpha-synuclein and synphilin-1 inclusions and the involvement of the cytoskeleton in their formation.

The aggregation of misfolded protein into amyloidic inclusions is a hallmark of several neurodegenerative disorders. For Parkinsons disease, one of the distinctive features is the presence of intraneuronal Lewy bodies, mainly consisting of aggregated a-synuclein and synphilin-1. In this project, we will use humanized yeast models to study the aggregation and cellular toxicity of a-synuclein and its interaction partner synphilin-1. We will track how small aggregates of these human proteins initiate and evolve into one or a few large cytoplasmic inclusions. The role of the yeast cytoskeleton as transport route directed towards the large protein aggregates will be an important area of focus. Next to the involvement of actin filaments and microtubuli, we will further characterize new cytoskeletal components, already identified in three independent screens. These new components include proteins identified using yeast deletion mutants as well as human proteins isolated from a hippocampal cDNA library. A second area of focus will be the nature of the inclusions themselves. We will characterize whether a-synuclein and synphilin-1 inclusions co-localize to JUNQ deposits and/or to IPOD deposits.

Keywords:JUNQ, IPOD, Aggregation, Synphilin-1, A-synuclein, Yeast, Parkinsons disease

Disciplines:Plant biology