These results are reminiscent to the phenotypes seen after depletion of cellular proteins involved in endosomal sorting and trafficking, such as Hrs, TSG101 and Vps24.48, 49 Endosomal abnormalities are among the earliest pathological features of AD and Down syndrome.50 Mutations of Rab7,51 of the guanine nucleotide exchange factor alsin52 and of Vps5453 cause neuropathy and motor neuron diseases in mammals. Here, TSG101 is linked to Alzheimer disease.