Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

Frontiers in Neuroscience

Anders Lindén¹  Tarja Malm²  Anthony P. Wright³  Kariem Ezzat³  Oskar Gustafsson³  Alberto J. Espay⁵  Andrea Sturchio⁵  Samir El Andaloussi⁶  Maja Malmberg⁷  Caroline Graff⁹ 

[1] 0Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden;A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland;Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden;Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden;Department of Neurology and Rehabilitation Medicine, James J and Joan A Gardner Center for Parkinson Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, United States;Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;SLU Global Bioinformatics Centre, Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden;Section of Virology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden;Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden;Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;

关键词: amyloid;    nucleation;    Alzheiemr’s;    Parkinson’s;    virus;    prion;   

DOI  :  10.3389/fnins.2020.00256

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown