Self-propagation of pathogenic protein aggregates in neurodegenerative diseases

Abstract

The prion paradigm – the hypothesis that the seeded aggregation of certain proteins is key to understanding age-related neurodegenerative disorders – is evaluated in relation to recent studies and disease models; the paradigm suggests a unifying pathogenic principle with broad relevance to a large class of currently intractable diseases. There is growing speculation that the pathophysiological features common to age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, and prion infections, such as Creutzfeldt–Jakob disease, may be key to our understanding of these conditions. In this Review, Mathias Jucker and Lary Walker consider recent work on the parallels between the self-propagating and misfolding protein aggregates associated with neurodegeneration and the infectious and self-seeding activities of prions. They conclude that the 'prion paradigm' linking these two groups of diseases could lead to a better understanding of the pathology and possible approaches to therapy for diseases that have so far proved intractable. 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.