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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

Sammanfattning

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.

Nyckelord

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

Publicerad i

Frontiers in Neuroscience
2020, Volym: 14, artikelnummer: 256Utgivare: FRONTIERS MEDIA SA

    Globala målen

    SDG3 God hälsa och välbefinnande

    UKÄ forskningsämne

    Neurovetenskaper

    Publikationens identifierare

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

    Permanent länk till denna sida (URI)

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