Our **data** links for the first time PIKfyve activity to the delivery of tau seeds into lysosomes and implicates it as a player in tau seeding, which highlights the role of lipid metabolism in disease (66). Loss of PI 3,5 P 2 in mice has been linked to neurodegeneration (67), while more recently it was shown that APP can bind and regulate the function of PIKfyve and consequently the generation of PI 3,5 P 2 (68,69). Of interest, PIKfyve inhibition has been show to rescue neurodegeneration in ALS patient iPSC-derived motor neurons and a C9orf72 ALS/FTD mouse model (70,71) implying that the beneficial action of PIKfyve inhibition might not be limited to Tau aggregates. Furthermore, the PIKfyve inhibitor Apilimod has been used in several phase I clinical trials for the treatment of Crohn's disease, non-Hodgkin lymphoma, and more recently in the prevention of COVID-19 (clinicaltrials.com, alternative names: STA-5326 and LAM-002). Besides MVB maturation to lysosomes, PIKfyve and PI 3,5 P 2 are also important for transport into the trans-Golgi network and for retromer function (72)(73)(74). Retromer stabilization using small-molecule chaperones can indeed reduce tau pathology in mouse models and tau phosphorylation in iPSC-derived human neurons (27,75), thereby strengthening the idea of modulation of endolysosomal function as a disease-modifying strategy.