title: Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease.
abstract: Mutations in ALS2, carrying three putative guanine exchange factor (GEF) domains, are causative for a juvenile, autosomal recessive form of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and infantile-ascending hereditary spastic paralysis. Endogenous ALS2 is shown here to be enriched in nervous tissue and to be peripherally bound to the cytoplasmic face of endosomal membranes, an association that requires the amino-terminal "RCC1 (regulator of chromatin condensation)-like" GEF domain. Disease-causing mutants and a naturally truncated isoform of ALS2 are shown to be rapidly degraded when expressed in cultured human cells, including lymphocytes derived from patients with ALS2 mutations. Thus, mutations in the ALS2 gene linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal GEF.
authors.affiliation: Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Christine
authors.initials: C
authors.lastname: Vande Velde
authors.forename: Eleonore
authors.initials: E
authors.lastname: Eymard-Pierre
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins; D011992:Endosomes / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D006801:Humans; D023421:Models, Animal; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000235:genetics*; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000737:chemistry; D051381:Rats
chemical_list: D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D010446:Peptide Fragments; C062521:RCC1 protein, human