Hadano Shinji, Kunita Ryota, Otomo Asako, Suzuki-Utsunomiya Kyoko, Ikeda Joh-E
Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Neurochem Int. 2007 Jul-Sep;51(2-4):74-84. doi: 10.1016/j.neuint.2007.04.010. Epub 2007 May 4.
ALS2 is a causative gene for a juvenile autosomal recessive form of motor neuron diseases (MNDs), including amyotrophic lateral sclerosis 2 (ALS2), juvenile primary lateral sclerosis, and infantile-onset ascending hereditary spastic paralysis. These disorders are characterized by ascending degeneration of the upper motor neurons with or without lower motor neuron involvement. Thus far, a total of 12 independent ALS2 mutations, which include a small deletion, non-sense mutation, or missense mutation spreading widely across the entire coding sequence, are reported. They are predicted to result in either premature termination of translation or substitution of an evolutionarily conserved amino acid. Thus, a loss of functions in the ALS2-coded protein accounts for motor dysfunction and/or degeneration in the ALS2-linked MNDs. The ALS2 gene encodes a novel 184kDa protein of 1657 amino acids, ALS2 or alsin, comprising three predicted guanine nucleotide exchange factor (GEF) domains: the N-terminal RCC1-like domain, the central Dbl homology and pleckstrin homology (DH/PH) domains, and the C-terminal vacuolar protein sorting 9 (VPS9) domain. In addition, eight consecutive membrane occupation and recognition nexus (MORN) motifs are noted in the region between DH/PH and VPS9 domains. ALS2 activates Rab5 small GTPase and involves in endosome/membrane trafficking and fusions in the cells, and also promotes neurite outgrowth in neuronal cultures. Further, a neuroprotective role for ALS2 against cytotoxicity; i.e., the mutant Cu/Zn-superoxide dismutase 1 (SOD1)-mediated toxicity, oxidative stress, and excitotoxicity, has recently been implied. This review outlines current understandings of the molecular and cellular functions of ALS2 and its related proteins on safeguarding the integrity of motor neurons, and sheds light on the molecular pathogenesis of MNDs as well as other conditions of neurodegenerative diseases.
ALS2是青少年常染色体隐性运动神经元疾病（MNDs）的致病基因，这些疾病包括肌萎缩侧索硬化症2型（ALS2）、青少年原发性侧索硬化症和婴儿期起病的上行性遗传性痉挛性截瘫。这些疾病的特征是上运动神经元的上行性变性，可伴有或不伴有下运动神经元受累。到目前为止，共报道了12种独立的ALS2突变，包括一个小缺失、无义突变或错义突变，广泛分布于整个编码序列。预计它们会导致翻译提前终止或进化保守氨基酸的替代。因此，ALS2编码蛋白的功能丧失导致了ALS2相关MNDs中的运动功能障碍和/或变性。ALS2基因编码一种由1657个氨基酸组成的新型184kDa蛋白，即ALS2或alsin，它包含三个预测的鸟嘌呤核苷酸交换因子（GEF）结构域：N端类RCC1结构域、中央Dbl同源和普列克底物蛋白同源（DH/PH）结构域以及C端液泡蛋白分选9（VPS9）结构域。此外，在DH/PH和VPS9结构域之间的区域发现了八个连续的膜占据和识别连接（MORN）基序。ALS2激活Rab5小GTP酶，并参与细胞内的内体/膜运输和融合，还促进神经元培养物中的神经突生长。此外，最近还暗示了ALS2对细胞毒性具有神经保护作用，即突变型铜/锌超氧化物歧化酶1（SOD1）介导的毒性、氧化应激和兴奋毒性。本综述概述了目前对ALS2及其相关蛋白在保护运动神经元完整性方面的分子和细胞功能的理解，并阐明了MNDs以及其他神经退行性疾病的分子发病机制。
