Regulation of endosomal motility and degradation by amyotrophic lateral sclerosis 2/alsin.
Regulation of endosomal motility and degradation by amyotrophic lateral sclerosis 2/alsin.
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DOI：
10.1186/1756-6606-2-23
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发表时间：
2009-07-24
期刊：
影响因子：
3.6
通讯作者：
Cai H
中科院分区：
文献类型：
--
作者：
Lai C;Xie C;Shim H;Chandran J;Howell BW;Cai H
alsin的功能障碍，特别是其推测的Rab5鸟嘌呤核苷酸交换因子活性，与一种幼年发病隐性家族性肌萎缩性侧索硬化症（ALS2）有关。已经产生了多系alsin敲除（ALS2-/-）小鼠来模拟这种疾病。然而，在ALS2-/-神经元中，rab5依赖性内吞作用是否发生改变尚不清楚。为了直接检测Rab5介导的ALS2-/-神经元内体运输，我们将绿色荧光蛋白（GFP）标记的Rab5引入培养的海马神经元，监测Rab5相关早期内体的形态和运动。在这里，我们报道rab5介导的内吞作用在ALS2-/-神经元中严重改变。在ALS2-/-神经元中观察到rab5阳性囊泡的过度积累，这与内体运动显著降低和内体向溶酶体转化的增加有关。因此，在ALS2-/-神经元中观察到内化谷氨酸受体的内核体/溶酶体依赖性降解显著增加。这些表型与野生型神经元中Rab5组成型活性形式诱导的内体运输异常非常相似。因此，我们的研究结果揭示了alsin在rab5介导的内体运输中的负调控机制，表明ALS2-/-神经元内体降解的增强可能是ALS2和相关运动神经元疾病中运动神经元变性的发病机制。
Dysfunction of alsin, particularly its putative Rab5 guanine-nucleotide-exchange factor activity, has been linked to one form of juvenile onset recessive familial amyotrophic lateral sclerosis (ALS2). Multiple lines of alsin knockout (ALS2-/-) mice have been generated to model this disease. However, it remains elusive whether the Rab5-dependent endocytosis is altered in ALS2-/- neurons. To directly examine the Rab5-mediated endosomal trafficking in ALS2-/- neurons, we introduced green fluorescent protein (GFP)-tagged Rab5 into cultured hippocampal neurons to monitor the morphology and motility of Rab5-associated early endosomes. Here we report that Rab5-mediated endocytosis was severely altered in ALS2-/-neurons. Excessive accumulation of Rab5-positive vesicles was observed in ALS2-/- neurons, which correlated with a significant reduction in endosomal motility and augmentation in endosomal conversion to lysosomes. Consequently, a significant increase in endosome/lysosome-dependent degradation of internalized glutamate receptors was observed in ALS2-/- neurons. These phenotypes closely resembled the endosomal trafficking abnormalities induced by a constitutively active form of Rab5 in wild-type neurons. Therefore, our findings reveal a negatively regulatory mechanism of alsin in Rab5-mediated endosomal trafficking, suggesting that enhanced endosomal degradation in ALS2-/- neurons may underlie the pathogenesis of motor neuron degeneration in ALS2 and related motor neuron diseases.
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