Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

Abstract

Amyloids are fibrillar protein aggregates associated with diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes and Creutzfeldt-Jakob disease. The process of amyloid polymerization involves three pathological protein transformations; from natively folded conformation to the cross-β conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-β conformation, the biophysical transformation can either take place spontaneously via a homogeneous nucleation mechanism (HON) or catalytically on an exogenous surface via a heterogeneous nucleation mechanism (HEN). Here, we postulate that the different nucleation pathways can serve as a mechanistic basis for an etiological classification of amyloidopathies, where hereditary forms generally follow the HON pathway, while sporadic forms follow seed-induced (prions) or surface-induced (including microbially induced) HEN pathways. Critically, the conformational and biophysical amyloid transformation results in loss-of-function (LOF) of the original natively folded and soluble protein. This LOF can, at least initially, be the mechanism of amyloid toxicity even before amyloid accumulation reaches toxic levels. By highlighting the important role of non-protein species in amyloid formation and LOF mechanisms of toxicity, we propose a generalized mechanistic framework that could help better understand the diverse etiology of amyloid diseases and offer new opportunities for therapeutic interventions, including replacement therapies.

Keywords: Alzheiemr’s; Parkinson’s; amyloid; nucleation; prion; protein-only hypothesis; virus.

FIGURE 1

(A) A schematic representation of the kinetics of amyloid aggregation with the rate-limiting nucleation phase that can be bypassed either by adding a preformed seed (prion) or by surface catalysis via HEN. (B) A schematic representation of the cross-β conformation, which is the core conformation of amyloids where two β-sheets are stacked opposite to each other forming the protofilament with the characteristic elongated amyloid morphology. While the cross-β conformation remains constant, variable β-sheet orientations or protofilament associations lead to different amyloid polymorphs. (C) A schematic representation of HEN where an exogenous surface catalyze amyloid nucleation via binding, concentrating, and inducing conformational changes in the bound peptides/proteins, which facilitate amyloid transformation. (D) A negatively stained transmission electron microscopy picture demonstrating direct interaction between the surface of a virus (HSV-1) and a growing amyloid protofilament of Aβ 1–42 peptide (unpublished image from the viral catalyzed nucleation experiments performed in the study of Ezzat et al. (2019), where HSV-1 was incubated with 50 μM Aβ 1–42 for 100 min. at 37°C). In the same publication, we demonstrated that HSV-1 accelerated amyloid aggregation in vitro and in vivo. The viral particle is indicated by a white arrow and the protofilament with a black arrow, bar = 200 nm.

FIGURE 2

Classification of different amyloid etiologies in relation to the nucleation mechanisms where hereditary forms are usually caused by genetic mutations that facilitate HON, while sporadic forms are mainly catalyzed via prions or pathological nucleating surfaces (PNSs) which can be of microbial or non-microbial origin. APP, amyloid precursor protein; SNCA, α-synuclein gene; TSE, transmissible spongiform encephalopathy; TBI, traumatic brain injury.