期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 27, 页码 9415-9420出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0803756105
关键词
Alzheimer's disease; inositol 5-phosphatase; phosphatidylinositol-4,5-bisphosphate; phosphatidylinositol phosphate kinase; synapse
资金
- NIDA NIH HHS [P30 DA018343] Funding Source: Medline
Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P-2] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P-2 balance is required for proper neurotransmission, the phosphoinositide phosphatase synaptojanin 1 is a key regulator of its metabolism. The underlying gene, SYNJ1, maps to human chromosome 21 and is thus a candidate for involvement in Down's syndrome (DS), a complex disorder resulting from the overexpression of trisomic genes. Here, we show that PtdIns(4,5)P-2 metabolism is altered in the brain of Ts65Dn mice, the most commonly used model of DS. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and is recapitulated in transgenic mice overexpressing Synj1 from BAC constructs. These transgenic mice also exhibit deficits in performance of the Morris water maze task, suggesting that PtdIns(4,5)P-2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.
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