Journal Article

Spreading of pathology in neurodegenerative diseases: a focus on human studies

Lee, Virginia M.-Y., Trojanowski, John Q., Brettschneider, Johannes, Tredici, Kelly Del

2015

Overview

Key Points Many neurodegenerative diseases share a common pathological hallmark: the accumulation of characteristic proteins into insoluble aggregates in vulnerable neurons and glial cells. Converging lines of evidence from cell culture studies and animal models indicate that progression of these diseases is driven by the template-directed misfolding, seeded aggregation and cell-to-cell transmission of characteristic disease-related proteins. Although such mechanisms of propagation are similar to prions, important differences to prions exists, namely the lack of inter-individual infectivity and the lack of zoonoses. Neuropathological studies in humans identified stereotypical patterns of pathology in various neurodegenerative diseases, and progression of these patterns can be correlated with increasing severity of the clinical phenotype, enabling the development of staging systems for these diseases. Human tissue pathology-staging studies are limited by the relative lack of early (prodromal) cases and by the fact that the resulting neuropathological data are, by definition, cross-sectional. Imaging biomarkers specific to the different disease proteins are necessary to validate the sequential involvement of different CNS regions proposed by human autopsy studies. Currently, the most promising markers are positron emission tomography ligands that should enable the in vivo detection and monitoring of the spread of protein pathology in longitudinal studies. Various neurodegenerative diseases are characterized by aggregates of pathological proteins, and increasing evidence suggests these disease-associated proteins may 'spread' via neuronal connections. Trojanowski and colleagues describe the molecular mechanisms of such spreading, and present the findings from neuropathological and imaging studies in humans that support this process. The progression of many neurodegenerative diseases is thought to be driven by the template-directed misfolding, seeded aggregation and cell–cell transmission of characteristic disease-related proteins, leading to the sequential dissemination of pathological protein aggregates. Recent evidence strongly suggests that the anatomical connections made by neurons — in addition to the intrinsic characteristics of neurons, such as morphology and gene expression profile — determine whether they are vulnerable to degeneration in these disorders. Notably, this common pathogenic principle opens up opportunities for pursuing novel targets for therapeutic interventions for these neurodegenerative disorders. We review recent evidence that supports the notion of neuron–neuron protein propagation, with a focus on neuropathological and positron emission tomography imaging studies in humans.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 59/78 / 631/378/1689/1283 / 631/378/1689/1285 / 631/378/1689/1718 / 631/80/470/460 / 82 / 82/1 / 82/51 / Amyotrophic lateral sclerosis / Animal Genetics and Genomics / Behavioral Sciences / Biological Techniques / Biomedicine / Brain - metabolism / Brain - pathology / Degeneration / Dementia / Disease / Disease Progression / Humans / Nervous system / Neurobiology / Neurodegenerative Diseases - metabolism / Neurodegenerative Diseases - pathology / Neurons - metabolism / Neurons - pathology / Neurosciences / Parkinson's disease / Pathology / Propagation / Proteins / review-article