[Recessive motor neuron diseases: mutations in the ALS2 gene and molecular pathogenesis for the upper motor...

We have initially identified a mutation in ALS2 as a causative for a juvenile autosomal recessive form of amyotrophic lateral sclerosis (ALS), termed ALS2 (OMIM 205100). ALS2 mutations also are causative for an autosomal recessive juvenile primary lateral sclerosis, and infantile-ascending hereditary spastic paralysis. To date, nine homozygous ALS2 mutaions from nine independent families have been identified. All of these mutations result in predicted premature translation termination caused by the recessive frameshift or nonsense mutation. ALS2 is a 184-kD protein comprising several putative guanine nucleotide exchange factor (GEF) domains [RLD; RCC1 like domain, DH. PH domain, VPS9; Vacuolar protein sorting 9 domain]. In vitro, ALS2 specifically binds to the small GTPase Rab5 and functions as a GEF for Rab5. Ectopic expression of full-length ALS2 has further implied an association with endosomal membranes mediated by the VPS9 domain, consistent with ALS2 involvement in endosomal trafficking and fusion in conjunction with the activation of Rab5. These results combined with our findings suggest that an obstruction of endosomal dynamics might underlie neuronal dysfunction and degeneration in ALS2, PLSJ, and HSP, as well as in a number of other motor neuron diseases.