Possible pathologic cascade of amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration (FTLD)-linked molecules

TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) induce a conjoint pathologic cascade of neurodegeneration that leads to ALS/FTLD with ubiquitin-positive inclusions. Ataxin-2 possibly promotes this cascade. Recent pathologic and biochemical evidence indicates that valosin containing protein (VCP) and progranulin (PGRN) may be located upstream of TDP-43 in the pathologic cascade. Cu/Zn SOD1 may contribute to an independent pathologic process or join the pathologic cascade downstream of TDP-43/FUS. The role of optineurin in the pathologic cascade remains to be elucidated.