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淀粉样β沉积，它是由淀粉样前体蛋白(APP)通过β-和伽马分泌酶裂解而产生的。γ-分泌酶复合体成分尼古丁(NCT)在γ-分泌酶复合体的组装和正确转运以及APP的识别中起着重要作用。未组装的NCT通过内质网1(Rer1)中的蛋白质滞留被回收或保留在内质网中。因此，我们假设，SynoViin(Syvn)是一种E3泛素连接酶，通过泛素化Rer1导致其随后的降解来调节伽马分泌酶复合体的组装或定位。我们的发现，在Syvn基因敲除的成纤维细胞中，由于其降解受到抑制，Rer1的水平增加了，这支持了这一假说。因此，Syvn很可能通过降解Rer1来调节伽马分泌酶复合体的组装，从而导致淀粉样β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.