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Cell:肌萎缩性侧索硬化症病因新发现

来源:生物谷 2008-06-19 10:40

专题:Cell专题

(封面图片:表达变异型VAP33的果蝇幼虫的腹神经索运动神经元。变异蛋白的过度表达在幼虫的运动神经元(绿色)中形成大量的细胞内胞质内含物(红/黄色)。图片中,人类脊柱的X射线图片被叠加到了果蝇腹神经索上。)

生物谷报道:人类的肌萎缩性侧索硬化症(amyotrophic lateral sclerosis,ALS)与一种蛋白变异有关。肌萎缩性侧索硬化症是一种神经退化性疾病,发病直接原因是运动神经元退化,而细胞内胞质内含物(cytoplasmic inclusion)则是这一疾病的一个重要特征。

VAP蛋白(包括人类的VAPB/ALS8蛋白、果蝇Drosophila VAP33蛋白、线虫C. elegans VPR-1蛋白)是一类特殊的蛋白质,它们是一个氨基末端主要精子蛋白域(major sperm protein,MSP)以及跨膜区的同源蛋白。MSP域与线虫C. elegans MSP蛋白相似,并由此得名。线虫MSP蛋白是一种产生精子的激素,它能结合到Eph受体上,并诱导精母细胞的成熟。此前研究表明,人类VAPB的MSP域发生的点突变(P56S)与肌萎缩性侧索硬化相关,但是导致这一疾病产生的发病机制目前尚不清楚。

在2008年6月13日出版的《细胞》(Cell)上,来自美国的一组科学家发表文章称,他们发现VAP蛋白的MSP域能发生分裂并分泌Eph受体的配合物。VAP33的P58S突变则能导致MSP域分泌受阻,泛素化(ubiquitination)发生,内质网内含物聚集,以及一种未折叠蛋白反应(unfolded protein response)产生等。在研究中,科学家们还提出VAP MSP域可能作为一种Eph受体的可扩散激素发生作用。

研究人员表示,他们的研究结果对于分析肌萎缩性侧索硬化症的发生机制以及病理过程十分重要。(生物谷www.bioon.com

生物谷推荐原始出处:

Cell,Vol 133, 963-977, 13 June 2008,Hiroshi Tsuda, Hugo J. Bellen

The Amyotrophic Lateral Sclerosis 8 Protein VAPB Is Cleaved, Secreted, and Acts as a Ligand for Eph Receptors

Hiroshi Tsuda,1 Sung Min Han,2 Youfeng Yang,2 Chao Tong,1 Yong Qi Lin,3 Kriti Mohan,1 Claire Haueter,3 Anthony Zoghbi,1 Yadollah Harati,4 Justin Kwan,4 Michael A. Miller,2 and Hugo J. Bellen1,3,5,

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
2 Department of Cell Biology, School of Medicine, University of Alabama Birmingham, AL 35294, USA
3 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
4 Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
5 Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA

Corresponding author
Hugo J. Bellen
hbellen@bcm.tmc.edu

Summary

VAP proteins (human VAPB/ALS8, Drosophila VAP33, and C. elegans VPR-1) are homologous proteins with an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to the Eph receptor and induces oocyte maturation. A point mutation (P56S) in the MSP domain of human VAPB is associated with Amyotrophic lateral sclerosis (ALS), but the mechanisms underlying the pathogenesis are poorly understood. Here we show that the MSP domains of VAP proteins are cleaved and secreted ligands for Eph receptors. The P58S mutation in VAP33 leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. We propose that VAP MSP domains are secreted and act as diffusible hormones for Eph receptors. This work provides insight into mechanisms that may impact the pathogenesis of ALS.

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