Understanding proteotoxicity of alpha- and gamma-synuclein in neuronal C. elegans models of neurodegeneration

Synucleopathies, such as Parkinson's Disease (PD), are neurodegenerative diseases characterised by the accumulation of alpha-synuclein (asyn) aggregates into Lewy Bodies in neurons, leading to toxicity and cell death. PD affects more than 10 million individuals worldwide, yet treatment options remain sparse. Excitingly, the supervisors' work recently identified two short segments (P1 and P2) in the N-terminal region of asyn that act as "master-controllers" driving aggregation. Deletion of these sequences prevents aggregation in vitro and protect C. elegans models of PD against proteotoxicity. Interestingly, a single point mutation in the P1 region also occurs in the related protein gamma synuclein (gsyn), which increases gsyn aggregation in an ALS patient cohort.

The project will investigate the molecular mechanism by which P1 and P2 control aggregation in asyn and gsyn in vitro and in C. elegans models of PD and ALS. Creating site-specific mutations we will identify key residues in P1/P2 that enhance/reduce aggregation, and investigate aggregation and toxicity in dopaminergic and motor neurons in C. elegans throughout aging of the worm as well as in human neuronal cell lines. Finally, we will explore the ability of affimers, that specifically target the P1/P2 regions, to prevent aggregation and toxicity in C. elegans and providing a translational opportunity for the development of therapeutic options.