Beyond prion-like spreading in neurodegenerative disease

To design effective therapies for neurodegenerative diseases, it is critical to understand the processes that trigger protein aggregation in sequential brain regions as the disease progresses. Aggregates formed in many neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are capable of seeding, leading to the proposal to regard them all as prion-like. We here argue that the utility of this classification is limited; the terms protein misfolding and aggregation-related diseases describe the general class of diseases, and the connotation of prion-like that the spreading of infectious prions is the rate-limiting process narrows the view of possible mechanisms. Instead, we suggest four factors along which to compare different diseases and model systems, providing a clearer basis to consider the different ways in which pathology can spread, account for factors beyond the aggregating protein, such as declining protein homeostasis with age, and understand the differences between model systems and human disease. HIGHLIGHTS: Four aspects by which to classify neurodegenerative diseases are proposed. Aggregates in health and inflammation are important factors. Prion-like spreading classification is not sufficient to capture the necessary nuance. Different diseases and model systems are dominated by different aspects.