A CRMP4‐dependent retrograde axon‐to‐soma death signal in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal non‐cell‐autonomous neurodegenerative disease characterized by the loss of motor neurons (MNs). Mutations in CRMP4 are associated with ALS in patients, and elevated levels of CRMP4 are suggested to affect MN health in the SOD1G93A‐ALS mouse model. However, the mechanism by which CRMP4 mediates toxicity in ALS MNs is poorly understood. Here, by using tissue from human patients with sporadic ALS, MNs derived from C9orf72‐mutant patients, and the SOD1G93A‐ALS mouse model, we demonstrate that subcellular changes in CRMP4 levels promote MN loss in ALS. First, we show that while expression of CRMP4 protein is increased in cell bodies of ALS‐affected MN, CRMP4 levels are decreased in the distal axons. Cellular mislocalization of CRMP4 is caused by increased interaction with the retrograde motor protein, dynein, which mediates CRMP4 transport from distal axons to the soma and thereby promotes MN loss. Blocking the CRMP4‐dynein interaction reduces MN loss in human‐derived MNs (C9orf72) and in ALS model mice. Thus, we demonstrate a novel CRMP4‐dependent retrograde death signal that underlies MN loss in ALS.SynopsisIdentification of an intracellular mechanism that mediates motor neuron (MN) death in Amyotrophic Lateral Sclerosis (ALS). CRMP4 binds the motor protein dynein and transports from distal axons to the soma where it promotes MN death. Blocking the CRMP4‐dynein interaction reduces MN death in human‐derived MNs (C9orf72) and in ALS mice.CRMP4 protein level is altered along ALS diseased motor unit.Dynein mediates CRMP4 mislocalization in motor neurons via specific CRMP4 motif.CRMP4‐dynein complexes are enhanced in ALS diseased MNs.CRMP4‐dynein complex formation facilitates selective neuronal loss in ALS.Dynein‐mediated CRMP4 redistribution from axons into the cell bodies of ALS‐affected motor neurons promotes selective neuronal toxicity in diverse ALS model‐ and patient‐derived cells.