RESEARCH: ALS2 gene mutation & PLS, HSP & ALS

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Unstable mutants in the peripheral endosomal membrane

component ALS2 cause early-onset motor neuron disease

Koji Yamanaka * , Vande Velde * , Eleonore

Eymard-Pierre , Enrico Bertini , Odile

Boespflug-Tanguy , and Don W. Cleveland *

*Ludwig Institute for Cancer Research and Departments

of Medicine and Neuroscience, University of California

at San Diego, 9500 Gilman Drive, La Jolla, CA 92093;

Institut National de la Santé et de la Recherche

Médicale Unité Mixte de Recherche 384 et Fédération de

Génétique Humaine Auvergne, Faculté de Médecine, 63001

Clermont-Ferrand, France; and Unit of Molecular

Medicine, Bambino Gesu Children’s Hospital, 00165

Rome, Italy

Edited by Fred H. Gage, The Salk Institute for

Biological Studies, San Diego, CA, and approved

October 28, 2003 (received for review August 15, 2003)

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.

SOURCE: Proc. Natl. Acad. Sci. USA, 2003 Dec 10 [Epub

ahead of print].

http://www.pnas.org/cgi/content/abstract/2635267100v1