Two Distinct Polymorphic Folding States of Self-Assembly of the Non-amyloid-β Component Differ in the Arrangement of the Residues.

Parkinson's disease is a degenerative disorder of the central nervous system. It is characterized by presence of Lewy bodies (LBs), in which the main components of the LBs are α-synuclein (AS) aggregates. The central domain of AS, known as the "non-amyloid-β component" (NAC) is responsible for the aggregation properties of AS. It is proposed that AS fibrillar structure is a well-packed cross-β structure of the NAC domains, while the N- and C-termini are disordered. Therefore, the study of the self-assembly of NAC domains is crucial in order to understand the molecular mechanisms of AS aggregation. This is a first study that illustrates two distinct polymorphic folding states of NAC that differ in the arrangement of the residues along the sequence. One of the polymorphic folding states reveals a conformational change that is similar to the other polymorphic folding state in the backbone shape but differs in the arrangement of the residues along the backbone. This work provides insight into the molecular mechanisms through which AS can self-assembled in two different pathways yielding a conformational change between the two polymorphic folding states.