The molecular chaperone HSC70 is required for multiple steps of clathrin-mediated endocytosis (CME). Yu et al. now show that CME is inhibited in prostate cancer cells and neuronal cells by aggregates of neurodegenerative disease-related proteins, including those formed by polyglutamine (polyQ) expansions such as Q82. Aggregates in the cytoplasm and in the nucleus inhibited CME by sequestering HSC70. Importantly, depletion of HSC70 using RNAi phenocopied the aggregate-induced inhibition of CME, and expressing HSC70 in cells that contain Q82 aggregates increased CME. This mechanism is relevant to neuropathologies, as CME of the neuron-specific cargo AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor was compromised in the presence of Q82, and CME was reduced in neurons containing aggregates of mutant huntingtin, which recruited HSC70.