Molecular Basis of Amyloid Polymorphism: Multiple Misfolding Pathways

Abstract

Protein misfolding and amyloid formation is implicated in numerous debilitating human diseases such as Alzheimer's, Parkinson's and Prion diseases [1]. More than 40 different types of polypeptides including intrinsically disordered as well as natively folded proteins were shown to be associated with amyloid diseases. Prion protein is unique in that the natively folded protein is able to form infectious aggregates with distinct molecular conformations (prion strains), which are proposed to underlie different disease phenotypes [2,3]. A central theme in the prion hypothesis is that the prion strain is encoded in the primary sequence, specifying amyloid conformation and disease phenotype. Mutations of the protein may induce different prion strains and cause distinct disease phenotypes. Recent studies have suggested that the prion-like mechanism is applicable to other amyloid diseases that also manifest diverse disease phenotypes [2,4]. It is intriguing that natively folded amyloidogenic proteins can form amyloid with distinct morphologies and molecular conformations depending on aggregation conditions, and the structural diversity may be linked to the phenotype variations of amyloid diseases [2]. Elucidation of the multiple amyloid formation processes leading to distinct amyloid conformations is, therefore, of critical importance in identifying therapeutic targets for the fatal human diseases. Amyloid formation is a complex process involving a series of steps where several intermediate states are populated (Figure 1). Amyloid formation of a natively folded protein can proceed via multiple misfolding and aggregation pathways, which may lead to diverse amyloid conformations [5,6]. The multiple misfolding pathways and polymorphism of amyloid imply that amyloid formation can result from different patterns of inter-residue interactions. The amyloids with distinct molecular conformations (amyloid strains) may have different toxic activities related to the phenotype diversity of amyloid diseases. Understanding the multiple misfolding and amyloid formation pathways is essential to unraveling molecular mechanism of amyloid polymorphism and phenotype diversity. In this hypothesis, the kinetic folding intermediate of the amyloidogenic proteins has an inherent aggregation propensity, and the pathogenic mutations alter the rugged landscape for the intermediate state and amyloid.