Alsin, the Product of ALS2 Gene, Suppresses SOD1 Mutant Neurotoxicity through RhoGEF Domain by Interacting with SOD1 Mutants

Mutation of the ALS2 gene encoding alsin is linked to the onset of autosomal recessive motor neuron diseases, including juvenile-onset amyotrophic lateral sclerosis (ALS). Alsin long form (LF) belongs to the family of the guanine nucleotide exchanging factor (GEF) for small GTPases. Expression of al...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-04, Vol.279 (18), p.19247-19256
Main Authors: Kanekura, Kohsuke, Hashimoto, Yuichi, Niikura, Takako, Aiso, Sadakazu, Matsuoka, Masaaki, Nishimoto, Ikuo
Format: Article
Language:English
Subjects:
Africa, Northern
Amyotrophic Lateral Sclerosis - etiology
Amyotrophic Lateral Sclerosis - genetics
Animals
Binding Sites
Cell Line, Tumor
Genetic Predisposition to Disease
Guanine Nucleotide Exchange Factors - chemistry
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - physiology
Humans
Mice
Middle East
Motor Neuron Disease - etiology
Motor Neuron Disease - genetics
Mutation
Neuroblastoma - pathology
Protein Binding
Rho Guanine Nucleotide Exchange Factors
Superoxide Dismutase - genetics
Superoxide Dismutase - toxicity
Superoxide Dismutase-1
Transfection
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Summary:Mutation of the ALS2 gene encoding alsin is linked to the onset of autosomal recessive motor neuron diseases, including juvenile-onset amyotrophic lateral sclerosis (ALS). Alsin long form (LF) belongs to the family of the guanine nucleotide exchanging factor (GEF) for small GTPases. Expression of alsin LF, but not alsin short form, protected motor neuronal cells from toxicity induced by mutants of the Cu/Zn-superoxide dismutase ( SOD1 ) gene, which cause autosomal dominant ALS. In contrast, expression of alsin did not suppress neurotoxicity by other neurodegenerative insults such as Alzheimer's disease-related genes. Deletion analysis of alsin LF demonstrated that the RhoGEF domain is essential for alsin-mediated neuroprotection. Furthermore, we found that alsin LF bound to SOD1 mutants, but not to wtSOD1, via the RhoGEF domain. Such functional and physical interaction between two ALS-related genes will become a promising clue to clarify the pathogenesis of ALS and other motor neuron diseases.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M313236200