The development of new diagnostic and therapeutic tools for AD based on regulation of the gamma-secretase complex assembly.

阿尔茨海默病的特征是β淀粉样蛋白沉积，β淀粉样蛋白是由淀粉样前体蛋白（APP）通过β和γ分泌酶裂解产生的。γ -分泌酶复合物组分nicastrin （NCT）在γ -分泌酶复合物的组装和适当运输以及APP的识别中起着重要作用。未组装的NCT通过内质网1蛋白保留（Rer1）被回收或保留在内质网中。因此，我们假设，E3泛素连接酶Synoviolin （Syvn）通过泛素化Rer1导致其随后的降解来调节γ -分泌酶复合物的组装或定位。我们发现，在syv敲除成纤维细胞中，由于抑制其降解，Rer1水平升高，这支持了这一假设。因此，Syvn可能通过降解Rer1来调节γ -分泌酶复合物的组装，从而导致β淀粉样蛋白的产生。

Alzheimer disease is characterized by the deposition of amyloid beta, which is generated from the amyloid precursor protein (APP) through its cleavage by beta- and gamma-secretases. The gamma-secretases complex component nicastrin (NCT) plays significant roles in the assembly and proper trafficking of the gamma-secretases complex and in the recognition of APP. Unassembled NCT is retrieved or retained in the ER by the protein Retention in endoplasmic reticulum 1 (Rer1). We hypothesized, therefore, that Synoviolin (Syvn), an E3 ubiquitin ligase, regulates the assembly or localization of the gamma-secretases complex by ubiquitinating Rer1 resulting in its subsequent degradation. Our findings that the level of Rer1 was increased in Syvn-knockout fibroblasts due to inhibition of its degradation support this hypothesis. Thus, it is likely that Syvn regulates the assembly of the gamma-secretases complex via the degradation of Rer1, which results in the generation of amyloid beta.