Alsin and the molecular pathways of amyotrophic lateral sclerosis
Alsin and the molecular pathways of amyotrophic lateral sclerosis
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DOI：
10.1007/s12035-007-0034-x
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发表时间：
2007-12-01
影响因子：
5.1
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
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作者：
Chandran, Jayanth;Ding, Jinhui;Cai, Huaibin
ALS 2基因的常染色体隐性突变导致运动功能障碍的临床谱，包括幼年型肌萎缩性侧索硬化症（ALS 2）、原发性侧索硬化症和遗传性痉挛性截瘫。由全长ALS 2基因编码的184-kDa alsin蛋白含有三个不同的鸟嘌呤核苷酸交换因子样结构域，这可能在疾病的病因学中起作用。多种体外生物化学和细胞生物学测定表明，alsin功能障碍通过Rab 5小GT3家族介导的机制影响内体运输。四个ALS 2缺陷型小鼠模型已经由不同的小组产生，并用于研究alsin缺乏的行为和病理影响。这些小鼠模型在很大程度上未能概括运动神经元疾病的特征，但在行为和病理学中观察到的细微缺陷有助于我们理解alsin和运动功能障碍之间的关系。在这篇综述中，我们总结了最近的临床和分子的报告，并试图把这些结果在运动神经元疾病的大背景下。
Autosomal recessive mutations in the ALS2 gene lead to a clinical spectrum of motor dysfunction including juvenile onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis, and hereditary spastic paraplegia. The 184-kDa alsin protein, encoded by the full-length ALS2 gene, contains three different guanine-nucleotide-exchange factor-like domains, which may play a role in the etiology of the disease. Multiple in vitro biochemical and cell biology assays suggest that alsin dysfunction affects endosome trafficking through a Rab5 small GTPase family-mediated mechanism. Four ALS2-deficient mouse models have been generated by different groups and used to study the behavioral and pathological impact of alsin deficiency. These mouse models largely fail to recapitulate hallmarks of motor neuron disease, but the subtle deficits that are observed in behavior and pathology have aided in our understanding of the relationship between alsin and motor dysfunction. In this review, we summarize recent clinical and molecular reports regarding alsin and attempt to place these results within the larger context of motor neuron disease.