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Research article2020Peer reviewedOpen access

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

Malmberg, Maja; Malm, Tarja; Gustafsson, Oskar; Sturchio, Andrea; Graff, Caroline; Espay, Alberto J.; Wright, Anthony P.; El Andaloussi, Samir; Linden, Anders; Ezzat, Kariem

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-beta conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-beta 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

amyloid; nucleation; Alzheiemr's; Parkinson's; virus; prion; protein-only hypothesis

Published in

Frontiers in Neuroscience
2020, Volume: 14, article number: 256Publisher: FRONTIERS MEDIA SA

    Sustainable Development Goals

    SDG3 Good health and well-being

    UKÄ Subject classification

    Neurosciences

    Publication identifier

    DOI: https://doi.org/10.3389/fnins.2020.00256

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/105746