Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition

Significance The aggregation of mutant proteins is pathologically implicated in a large number of neuropathies, including Huntington disease and ALS. Although the appearance of protein aggregates is known to sequester other proteins, how this results in the gain-of-function toxicity in these diseases is unclear. Here, we show that the aggregation of disease-associated proteins causes the reversible collapse of clathrin-mediated endocytosis (CME) and inhibits the internalization of membrane receptors that affect neuronal function. CME inhibition occurs through aggregate-mediated sequestration of the molecular chaperone heat shock cognate protein 70, which is essential for CME. We propose that a toxic “tug-of-war” occurs between aggregates and endogenous client proteins for available chaperones, leading to the collapse of multiple cellular processes in neurodegeneration and other protein conformation diseases.