@article{7a461cd39129496b8b34129299c1b4b6,
title = "Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome",
abstract = "Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27-/-mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27 +/-mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein β (C/EBPβ) in Down's syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis.",
author = "Xin Wang and Yingjun Zhao and Xiaofei Zhang and Hedieh Badie and Ying Zhou and Yangling Mu and Loo, {Li Shen} and Lei Cai and Thompson, {Robert C.} and Bo Yang and Yaomin Chen and Johnson, {Peter F.} and Chengbiao Wu and Guojun Bu and Mobley, {William C.} and Dongxian Zhang and Gage, {Fred H.} and Barbara Ranscht and Zhang, {Yun Wu} and Lipton, {Stuart A.} and Wanjin Hong and Huaxi Xu",
note = "Funding Information: Medical Research Institute) for helping with statistical analysis, K. Saylor (US National Institutes of Health) for C/EBPβ knockout mouse breeding and tissue collection and A. Brzozowska-Prechtl and L. Lacarra for technical help. This work was supported in part by US National Institutes of Health grants (R01 AG038710, R01 AG021173, R01 NS046673, R01 AG030197 and R01 AG044420 to H.X.; and P01 HD29587, P01 ES016738, P30 NS076411 to S.A.L.) and grants from the Alzheimer{\textquoteright}s Association (to H.X. and Y. Zhang), the American Health Assistance Foundation (to H.X.), National Natural Science Foundation of China (30973150 and 81161120496 to Y. Zhang), the 973 Prophase Project (2010CB535004 to Y. Zhang) and Natural Science Funds for Distinguished Young Scholar of Fujian Province (2009J06022 to Y. Zhang). Y. Zhang is supported by the Program for New Century Excellent Talents in Universities (NCET), the Fundamental Research Funds for the Central Universities and Fok Ying Tung Education Foundation. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, US National Cancer Institute and Center for Cancer Research.",
year = "2013",
month = apr,
doi = "10.1038/nm.3117",
language = "English (US)",
volume = "19",
pages = "473--480",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}