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.
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We thank D. Eisenberg, H. LeVine, A. Aguzzi, J. Collinge, R. Rosen, Y. Eisele, A. Mehta, M. Gearing, J. Manson, M. Neumann, and the members of our laboratories for critical discussions and comments. The help of H. Braak with Fig. 1, and the help of S. Eberle with the manuscript and figures is gratefully acknowledged. 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.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors declare no competing financial interests.
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Jucker, M., Walker, L. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013). https://doi.org/10.1038/nature12481
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