Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments.
Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments.
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DOI：
10.1186/s13024-017-0165-0
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发表时间：
2017-03-10
影响因子：
15.1
通讯作者：
De Strooper B
中科院分区：
文献类型：
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作者：
Guix FX;Sannerud R;Berditchevski F;Arranz AM;Horré K;Snellinx A;Thathiah A;Saido T;Saito T;Rajesh S;Overduin M;Kumar-Singh S;Radaelli E;Corthout N;Colombelli J;Tosi S;Munck S;Salas IH;Annaert W;De Strooper B
非家族性阿尔茨海默病 (AD) 中 Aβ 肽积累的机制仍然难以捉摸。四跨膜蛋白家族的蛋白质通过与 γ 分泌酶相互作用来调节 Aβ 的产生。我们寻找 AD 大脑中表达发生改变的四跨膜蛋白。在体外研究了所选四跨膜蛋白的功能，并在体内证实了我们研究结果的生理相关性。 Tetraspanin-6 (TSPAN6) 在 AD 大脑中增加，细胞中的过度表达对淀粉样前体蛋白 (APP) 代谢产生矛盾的影响，同时增加 APP-C 末端片段 (APP-CTF) 和 Aβ 水平。 TSPAN6 影响自噬体-溶酶体融合，减缓 APP-CTF 的降解。 TSPAN6 还招募细胞质的外泌体形成接头 Syntenin，从而增加含有 APP-CTF 的外泌体的分泌。 TSPAN6 是溶酶体依赖性降解和外泌体介导的 APP-CTF 分泌之间分歧的关键参与者。这证实了自噬体/溶酶体途径在 APP 代谢中的核心作用，并表明 TSPAN6 在 APP-CTF 周转中发挥着关键作用。本文的在线版本 (doi:10.1186/s13024-017-0165-0) 包含补充材料，可供授权用户使用。
The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo. Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF. TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover. The online version of this article (doi:10.1186/s13024-017-0165-0) contains supplementary material, which is available to authorized users.