Sorting Nexin 27 Regulates Aß Production through Modulating ?-Secretase Activity
Article Nov 06, 2014
Xin Wang, Timothy Huang, Yingjun Zhao, Qiuyang Zheng, Robert C. Thompson, Guojun Bu, Yun-wu Zhang, Wanjin Hong, Huaxi Xu
Summary: Patients with Down syndrome (DS) invariably develop Alzheimer’s disease (AD) pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here, we report a function of SNX27 in regulating β-amyloid (Aβ) generation by modulating γ-secretase activity. Downregulation of SNX27 using RNAi increased Aβ production, whereas overexpression of full-length SNX27, but not SNX27ΔPDZ, reversed the RNAi-mediated Aβ elevation. Moreover, genetic deletion of Snx27 promoted Aβ production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV) vector reduced hippocampal Aβ levels in a transgenic AD mouse model. SNX27 associates with the γ-secretase complex subunit presenilin 1; this interaction dissociates the γ-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Aβ-dependent pathogenesis in both DS and AD.
New Crystal Structure of (Ph)PINK1 Aids Understanding of Early Onset Parkinson’sArticle
Scientists have determined the crystal structure of PhPINK1 bound to it's substrate ubiquitin. Mutations of PINK1 are associated with early onset Parkinson's disease and it is expected that this information will help the design of Parkinson's therapeutics.READ MORE