（封面圖片：表達變異型VAP33的果蠅幼蟲的腹神經(jīng)索運動神經(jīng)元。變異蛋白的過度表達在幼蟲的運動神經(jīng)元（綠色）中形成大量的細胞內(nèi)胞質內(nèi)含物（紅/黃色）,。圖片中，人類脊柱的X射線圖片被疊加到了果蠅腹神經(jīng)索上,。）
生物谷報道：人類的肌萎縮性側索硬化癥（amyotrophic lateral sclerosis，ALS）與一種蛋白變異有關。肌萎縮性側索硬化癥是一種神經(jīng)退化性疾病,，發(fā)病直接原因是運動神經(jīng)元退化,，而細胞內(nèi)胞質內(nèi)含物（cytoplasmic inclusion）則是這一疾病的一個重要特征。
VAP蛋白（包括人類的VAPB/ALS8蛋白,、果蠅Drosophila VAP33蛋白,、線蟲C. elegans VPR-1蛋白）是一類特殊的蛋白質，它們是一個氨基末端主要精子蛋白域（major sperm protein,，MSP）以及跨膜區(qū)的同源蛋白,。MSP域與線蟲C. elegans MSP蛋白相似，并由此得名,。線蟲MSP蛋白是一種產(chǎn)生精子的激素,，它能結合到Eph受體上，并誘導精母細胞的成熟,。此前研究表明，人類VAPB的MSP域發(fā)生的點突變（P56S）與肌萎縮性側索硬化相關,，但是導致這一疾病產(chǎn)生的發(fā)病機制目前尚不清楚,。
在2008年6月13日出版的《細胞》（Cell）上，來自美國的一組科學家發(fā)表文章稱,，他們發(fā)現(xiàn)VAP蛋白的MSP域能發(fā)生分裂并分泌Eph受體的配合物,。VAP33的P58S突變則能導致MSP域分泌受阻，泛素化（ubiquitination）發(fā)生,，內(nèi)質網(wǎng)內(nèi)含物聚集，以及一種未折疊蛋白反應（unfolded protein response）產(chǎn)生等,。在研究中,，科學家們還提出VAP MSP域可能作為一種Eph受體的可擴散激素發(fā)生作用。
研究人員表示,，他們的研究結果對于分析肌萎縮性側索硬化癥的發(fā)生機制以及病理過程十分重要,。（生物谷www.bioon.com）
生物谷推薦原始出處：
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
[email protected]
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.
