Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of progressive neurodegenerative disorders characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord.While most of the cases reported are sporadic, 5-10% are familial.Thus far, more than 15 ALS-causative genes have been identified.In 2001, we identified ALS2 as a causative gene for a juvenile autosomal recessive form of motor neuron diseases (MNDs) including amyotrophic lateral sclerosis 2.A total of 17 independent ALS2 mutations are reported.They are predicted to result in either premature termination of translation or substitution of an evolutionarily conserved amino acid.Thus, a loss of functions in the ALS2-coded protein accounts for motor dysfunction and/or degeneration in the ALS2-linked MNDs.The ALS2 gene encodes a 184 kDa protein of 1657 amino acids, ALS2 or alsin, comprising three predicted guanine nucleotide exchange factor (GEF) domains.ALS2 activates Rab5 small GTPase and involves in endosome/membrane trafficking and fusions in the cells, and also promotes neurite outgrowth in neurons.We have recently revealed that loss of ALS2 exacerbates the mutant SOD 1-associated ALS/MND symptoms in mice.Further, loss of ALS2 impairs the maturation of autophagosomes, which causes the lowering of the autophagic flux, thereby accumulating immature vesicles and insoluble misfolded proteins under stress conditions.Thus, disturbance of the autophagy-endolysosomal trafficking by ALS2 loss might be a causative of the manifestations ofALS2-linked MNDs in human.Here, I outline the current understandings of the molecular and cellular functions of ALS2, and dysfunction of the autophagyendolysosomal system in ALS/MNDs.