• Defective endosomal proteostasis is a hallmark of CHMP2BIntron5 FTD/ALS. • CHMP2BIntron5 causes neuronal dysfunction in Drosophila and mammalian models. • FDA approved compound UDCA rescues neuronal dysfunction in both models. • UDCA treatment does not rescue endosome function or excess ubiquitinated protein. • UDCA treatment highlights glutathione as a novel regulator of CHMP2BIntron5 pathology.