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  current news   Press   selected story    
     
  25 April 2013  
  Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome
 
 



Authors
Xin Wang1,2, Yingjun Zhao1,3, Xiaofei Zhang1, Hedieh Badie4, Ying Zhou2, Yangling Mu5, Li Shen Loo6, Lei Cai6, Robert C Thompson1, Bo Yang1, Yaomin Chen1, Peter F Johnson7, Chengbiao Wu8, Guojun Bu3, William C Mobley8, Dongxian Zhang1, Fred H Gage5, Barbara Ranscht4, Yun-wu Zhang1,3, Stuart A Lipton1,8, Wanjin Hong6,9, & Huaxi Xu1,3.

1 - Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research      Institute, La Jolla, California, USA.
2 - Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla,      California, USA.
3 - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College,      Xiamen University, Xiamen, China.
4 - Tumor Microenvironment Program, Sanford-Burnham Medical Research Institute, La Jolla, California,      USA.
5 - Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, USA.
6 - Institute of Molecular and Cell Biology, Singapore.
7 - Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute-Frederick,      National Institutes of Health, Frederick, Maryland, USA.
8 - Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
9 - Institute for Biomedical Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen,      China.

Published in Nat Med. 2013 Apr;19(4):473-80.
To read more, please click here.

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.

Figure Legend: SNX27 is required for maintaining synaptic function through modulation of NMDAR and AMPAR recycling. In Down's syndrome, higher than normal amounts of the Chromosome 21-encoded miR-155 suppresses the expression of C/EBPβ, which results in reduced amounts of SNX27 and eventually contributes to synaptic deficits in Down's syndrome brains.

For more information on on Wanjin HONG’s laboratory, please click here.