Loss of peptidyl prolyl-isomerase activity of the cyclophilin domain (CY) in Ranbp2 promotes the downregulation of the proteostasis of the ALS-causing substrate, hnRNPA2B1, in inner retinal neurons (Cho et al., 2014), whereas orthosteric inhibitors of the peptidyl prolyl-isomerase activity of CY of Ranbp2 downregulate hnRNPA2B1 proteostasis (Cho et al., 2015b). Here, RANBP2 is linked to amyotrophic lateral sclerosis.