Kanekura Kohsuke, Hashimoto Yuichi, Niikura Takako, Aiso Sadakazu, Matsuoka Masaaki, Nishimoto Ikuo
Departments of Pharmacology and Anatomy, KEIO University School of Medicine, Life Science Research Building, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
J Biol Chem. 2004 Apr 30;279(18):19247-56. doi: 10.1074/jbc.M313236200. Epub 2004 Feb 16.
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.
编码alsin的ALS2基因突变与常染色体隐性运动神经元疾病的发病相关，包括青少年型肌萎缩侧索硬化症（ALS）。Alsin长型（LF）属于小GTP酶的鸟嘌呤核苷酸交换因子（GEF）家族。Alsin LF而非Alsin短型的表达，可保护运动神经元细胞免受由导致常染色体显性ALS的铜/锌超氧化物歧化酶（SOD1）基因突变体诱导的毒性影响。相比之下，Alsin的表达并不能抑制其他神经退行性损伤（如阿尔茨海默病相关基因）所导致的神经毒性。Alsin LF的缺失分析表明，RhoGEF结构域对于Alsin介导的神经保护作用至关重要。此外，我们发现Alsin LF通过RhoGEF结构域与SOD1突变体结合，但不与野生型SOD1结合。这两个与ALS相关基因之间的这种功能和物理相互作用，将成为阐明ALS和其他运动神经元疾病发病机制的一个有前景的线索。
