How sequence specific changes in the N-terminus of synucleins control their aggregation

The intrinsically disordered protein (IDP) alpha-synuclein (αSyn) is known to be involved in neurodegenerative disorders such as Parkinson’s disease (PD) which affects more than 10 million people worldwide. Patients show multiple motor (e.g. tremor, lack of coordination) and non-motor (e.g. depression, anxiety) symptoms, as well as pathological indicators, characterised by the loss of dopaminergic neurons and the formation of aggregated αSyn-containing Lewy bodies in the brain. Understanding the process of amyloid formation from the highly dynamic αSyn monomer to highly ordered fibrils, formed by β-sheets, is therefore crucial. The central part of the αSyn sequence contains the non-amyloid β-component (NAC) region crucial for aggregation. In this thesis, the importance of regions N-terminally flanking NAC is demonstrated and characterised in detail. Using bioinformatics, aggregation assays, in vivo systems, mutations, and NMR led to the identification of a 7-residue sequence, named P1 (residues 36GVLYVGS42) that modulates aggregation and function (in synergy with P2 (residues 45KEGVVHGVATVAE57)) of full-length αSyn.