Journal
NATURE MEDICINE
Volume 19, Issue 4, Pages 473-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3117
Keywords
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Funding
- US National Institutes of Health [R01 AG038710, R01 AG021173, R01 NS046673, R01 AG030197, R01 AG044420, P01 HD29587, P01 ES016738, P30 NS076411]
- Alzheimer's Association
- American Health Assistance Foundation
- National Natural Science Foundation of China [30973150, 81161120496]
- 973 Prophase Project [2010CB535004]
- Natural Science Funds for Distinguished Young Scholar of Fujian Province [2009J06022]
- Program for New Century Excellent Talents in Universities (NCET)
- Fundamental Research Funds for the Central Universities
- Fok Ying Tung Education Foundation
- Intramural Research Program of the US National Institutes of Health, US National Cancer Institute and Center for Cancer Research
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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 beta (C/EBP beta) in Down's syndrome brains and identify C/EBP beta as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBP beta, 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.
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