Neurodegeneration emerges at a cellular tipping point between aggregate accumulation and removal

Abstract

Protein aggregates are a hallmark of pathology across neurodegenerative diseases. Yet, the disconnect between molecular-level aggregation and the emergence of disease severely limits mechanistic understanding of neurodegeneration. Here, we bridge this disconnect by showing that a cellular tipping point emerges as a universal feature across diseases from the competition between aggregate accumulation and removal. We map the resulting cellular phase transition with our high-throughput live-cell assay, measuring the tipping point that separates healthy cells from those burdened with large aggregate loads. Using super-resolution imaging of brain tissue from Alzheimer's and Parkinson's disease, we quantify how the crucial balance of accumulation and removal is shifted in disease. Combined with in vitro aggregation kinetics, we then validate our framework by predicting how designed aggregation inhibitors shift the tipping point to restore cellular homeostasis. Our results provide a mechanistic framework to connect molecular-level aggregation to disease states, paving the way for a quantitative, unified understanding of neurodegeneration and enabling predictions of the complex, non-linear dynamics that govern therapeutic efficacy.