Self-propagation of pathogenic protein aggregates in neurodegenerative diseases

• Type of Material: Article
• Authors: Mathias Jucker, University of Tübingen; Lary C Walker, Emory University
• Language: English
• Date: 2013-09-05
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013, Rights Managed by Nature Publishing Group
• Final Published Version (URL): http://www.nature.com/nature/journal/v501/n7465/full/nature12481.html
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 501
• Issue: 7465
• Start Page: 45
• End Page: 51
• Grant/Funding Information: This work was supported by grants from the Competence Network on Degenerative Dementias (BMBF-01GI0705), ALZKULT (BMBF-031A198A), NGFN2 (BMBF-01GS08131), and anonymous foundations (to M.J.), and by National Institutes of Health grants R21AG040589, P51RR165, P51OD11132, and the CART Foundation (to L.C.W.).
• Research Categories: Biology, Neuroscience

Abstract

For several decades scientists have speculated that the key to understanding age-related neurodegenerative disorders may be found in the unusual biology of the prion diseases. Recently, owing largely to the advent of new disease models, this hypothesis has gained experimental momentum. In a remarkable variety of diseases, specific proteins have been found to misfold and aggregate into seeds that structurally corrupt like proteins, causing them to aggregate and form pathogenic assemblies ranging from small oligomers to large masses of amyloid. Proteinaceous seeds can therefore serve as self-propagating agents for the instigation and progression of disease. Alzheimer’s disease and other cerebral proteopathies seem to arise from the de novo misfolding and sustained corruption of endogenous proteins, whereas prion diseases can also be infectious in origin. However, the outcome in all cases is the functional compromise of the nervous system, because the aggregated proteins gain a toxic function and/or lose their normal function. As a unifying pathogenic principle, the prion paradigm suggests broadly relevant therapeutic directions for a large class of currently intractable diseases.