Here, using induced human pluripotent stem cell (iPSC) derived spinal neurons (iPSNs) and postmortem human tissues, we show that the nuclear expression of VPS4, but not CHMP4B or CHMP2B, is pathologically increased in C9orf72 ALS/FTD and sALS human neurons. Here, CHMP2B is linked to amyotrophic lateral sclerosis.