Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1-expressing mouse ALS model by disturbing endolysosomal trafficking.
Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1-expressing mouse ALS model by disturbing endolysosomal trafficking.
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DOI：
10.1371/journal.pone.0009805
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发表时间：
2010-03-22
期刊：
影响因子：
3.7
通讯作者：
Ikeda JE
中科院分区：
文献类型：
--
作者：
Hadano S;Otomo A;Kunita R;Suzuki-Utsunomiya K;Akatsuka A;Koike M;Aoki M;Uchiyama Y;Itoyama Y;Ikeda JE
ALS 2/alsin是一个鸟嘌呤核苷酸交换因子的小GT受体Rab 5和参与巨胞饮相关的内体融合和运输，和神经突生长。ALS 2缺陷导致许多青少年隐性运动神经元疾病（MND）。最近，已经显示ALS 2在针对MND相关的病理损伤的神经保护中起作用，例如由突变的Cu/Zn超氧化物歧化酶（SOD 1）诱导的毒性。然而，ALS 2相关细胞功能与其神经保护作用之间关系的分子机制仍不清楚。为了解决这个问题，我们研究了突变SOD 1表达小鼠的表型修饰的分子和病理学基础的ALS 2损失。在SOD 1H 46 R转基因小鼠中，而不是SOD 1G 93 A转基因小鼠中，Als 2基因缺失加重了突变型SOD 1相关疾病的症状，如体重减轻和运动功能障碍，导致早期死亡。光镜和电镜检查显示，在早期甚至症状前SOD 1H 46 R小鼠中存在变性和/或肿胀的脊髓轴突积累颗粒状聚集体和自噬体样囊泡。此外，不溶性高分子量SOD 1、多聚泛素化蛋白和大自噬相关蛋白（如多聚泛素结合蛋白p62/SQSTM 1和轻链3（LC 3-II）的脂化形式）的积累增强，出现在ALS 2缺陷型SOD 1H 46 R小鼠中。有趣的是，ALS 2与LC 3和p62共定位，部分与SOD 1共定位在自噬体/内体混合区室上，并且ALS 2的丢失显著降低了培养细胞中LC 3和p62的溶酶体依赖性清除。基于这些观察结果，尽管在不同突变体SOD 1表达ALS模型中对ALS 2损失的独特易感性的分子基础仍然难以捉摸，但ALS 2损失对内溶酶体系统的干扰可能通过加速脊髓中未成熟囊泡和错误折叠蛋白的积累而加剧SOD 1H 46 R介导的神经毒性。我们认为ALS 2通过内体和自噬体的融合参与内溶酶体的运输，从而调节体内内溶酶体蛋白的降解。
ALS2/alsin is a guanine nucleotide exchange factor for the small GTPase Rab5 and involved in macropinocytosis-associated endosome fusion and trafficking, and neurite outgrowth. ALS2 deficiency accounts for a number of juvenile recessive motor neuron diseases (MNDs). Recently, it has been shown that ALS2 plays a role in neuroprotection against MND-associated pathological insults, such as toxicity induced by mutant Cu/Zn superoxide dismutase (SOD1). However, molecular mechanisms underlying the relationship between ALS2-associated cellular function and its neuroprotective role remain unclear. To address this issue, we investigated the molecular and pathological basis for the phenotypic modification of mutant SOD1-expressing mice by ALS2 loss. Genetic ablation of Als2 in SOD1H46R, but not SOD1G93A, transgenic mice aggravated the mutant SOD1-associated disease symptoms such as body weight loss and motor dysfunction, leading to the earlier death. Light and electron microscopic examinations revealed the presence of degenerating and/or swollen spinal axons accumulating granular aggregates and autophagosome-like vesicles in early- and even pre-symptomatic SOD1H46R mice. Further, enhanced accumulation of insoluble high molecular weight SOD1, poly-ubiquitinated proteins, and macroautophagy-associated proteins such as polyubiquitin-binding protein p62/SQSTM1 and a lipidated form of light chain 3 (LC3-II), emerged in ALS2-deficient SOD1H46R mice. Intriguingly, ALS2 was colocalized with LC3 and p62, and partly with SOD1 on autophagosome/endosome hybrid compartments, and loss of ALS2 significantly lowered the lysosome-dependent clearance of LC3 and p62 in cultured cells. Based on these observations, although molecular basis for the distinctive susceptibilities to ALS2 loss in different mutant SOD1-expressing ALS models is still elusive, disturbance of the endolysosomal system by ALS2 loss may exacerbate the SOD1H46R-mediated neurotoxicity by accelerating the accumulation of immature vesicles and misfolded proteins in the spinal cord. We propose that ALS2 is implicated in endolysosomal trafficking through the fusion between endosomes and autophagosomes, thereby regulating endolysosomal protein degradation in vivo.
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影响因子：
11.2
作者：
Jacquier, Arnaud;Buhler, Emmanuelle;Haase, Georg
通讯作者：
Haase, Georg
影响因子：
4.8
作者：
Kanekura, K;Hashimoto, Y;Matsuoka, M
通讯作者：
Matsuoka, M
影响因子：
4.8
作者：
Kabuta, Tomohiro;Suzuki, Yasuyuki;Wada, Keiji
通讯作者：
Wada, Keiji
DOI：
10.1016/j.molbrainres.2004.07.002
发表时间：
2004-11-04
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Alexander, GM;Erwin, KL;Heiman-Patterson, TD
通讯作者：
Heiman-Patterson, TD
影响因子：
4.7
作者：
Gal J;Ström AL;Kwinter DM;Kilty R;Zhang J;Shi P;Fu W;Wooten MW;Zhu H
通讯作者：
Zhu H