Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease

Koji Yamanaka, Christine Vande Velde, Eleonore Eymard-Pierre, Enrico Bertini, Odile Boespflug-Tanguy, Don W. Cleveland

Research output: Contribution to journalArticle

68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)16041-16046
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number26
DOIs
Publication statusPublished - Dec 23 2003

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Motor Neuron Disease
Guanine
Membranes
Mutation
Nerve Tissue
Muscle Spasticity
Protein Stability
Paralysis
Chromatin
Cultured Cells
Protein Isoforms
Juvenile Amyotrophic Lateral Sclerosis 2
Lymphocytes
Genes

ASJC Scopus subject areas

  • Genetics
  • General

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Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. / Yamanaka, Koji; Vande Velde, Christine; Eymard-Pierre, Eleonore; Bertini, Enrico; Boespflug-Tanguy, Odile; Cleveland, Don W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 26, 23.12.2003, p. 16041-16046.

Research output: Contribution to journalArticle

Yamanaka, Koji ; Vande Velde, Christine ; Eymard-Pierre, Eleonore ; Bertini, Enrico ; Boespflug-Tanguy, Odile ; Cleveland, Don W. / Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 26. pp. 16041-16046.
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