Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking
Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking
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DOI：
10.1093/hmg/ddi440
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发表时间：
2006-01-15
影响因子：
3.5
通讯作者：
Ikeda, JE
中科院分区：
文献类型：
--
作者：
Hadano, S;Benn, SC;Ikeda, JE
ALS 2/alsin是小G蛋白Rab 5的鸟嘌呤核苷酸交换因子（Rab 5GEFs）的成员，其作为内吞途径的调节剂。人类ALS 2的功能丧失突变导致了许多青少年隐性运动神经元疾病（MND）。然而，ALS 2在体内的正常生理作用和运动功能障碍的分子机制仍然是未知的。为了解决这些问题，我们已经产生了Als 2基因破坏的纯合小鼠。在21月龄内观察到的Als 2缺失小鼠没有表现出明显的发育、生殖或运动异常。然而，免疫组织化学和电生理分析确定了一个年龄依赖性的，缓慢进行性的小脑浦肯野细胞的损失和脊髓运动神经元与星形胶质细胞增多症和小胶质细胞活化的障碍，表明在Als 2-null小鼠亚临床运动系统功能障碍。此外，定量表皮生长因子（EGF）摄取分析鉴定了Als 2缺失成纤维细胞中显著更小尺寸的EGF阳性内体，表明细胞中内体/囊泡运输的改变。总的来说，虽然ALS 2的丢失不会在小鼠中产生严重的疾病表型，但这些Als 2缺失动物应该提供有用的模型，以了解内体动力学与大神经元（如浦肯野细胞和脊髓运动神经元）的长期活力之间的相互作用。
ALS2/alsin is a member of guanine nucleotide exchange factors for the small GTPase Rab5 (Rab5GEFs), which act as modulators in endocytic pathway. Loss-of-function mutations in human ALS2 account for a number of juvenile recessive motor neuron diseases (MNDs). However, the normal physiological role of ALS2 in vivo and the molecular mechanisms underlying motor dysfunction are still unknown. To address these issues, we have generated mice homozygous for disruption of the Als2 gene. The Als2-null mice observed through 21 months of age demonstrated no obvious developmental, reproductive or motor abnormalities. However, immunohistochemical and electrophysiological analyses identified an age-dependent, slowly progressive loss of cerebellar Purkinje cells and disturbance of spinal motor neurons associated with astrocytosis and microglial cell activation, indicating a subclinical dysfunction of motor system in Als2-null mice. Further, quantitative epidermal growth factor (EGF)-uptake analysis identified significantly smaller-sized EGF-positive endosomes in Als2-null fibroblasts, suggesting an alteration of endosome/vesicle trafficking in the cells. Collectively, while loss of ALS2 does not produce a severe disease phenotype in mice, these Als2-null animals should provide a useful model with which to understand the interplay between endosomal dynamics and the long-term viability of large neurons such as Purkinje cells and spinal motor neurons.