Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome.
Document Type
Article
Publication Date
2008
Keywords
Brain, Cognition-Disorders, Disease-Models-Animal, Down-Syndrome, Gene-Dosage, Homeostasis, Learning, Male, Maze-Learning, Mice-Inbred-C57BL, Mice-Transgenic, Nerve-Tissue-Proteins, Phosphatidylinositol-45-Diphosphate, Phosphoric-Monoester-Hydrolases
First Page
9415
Last Page
9420
JAX Source
Proc Natl Acad Sci U S A 2008 Jul; 105(27):9415-20.
Abstract
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.
Recommended Citation
Voronov SV,
Frere SG,
Giovedi S,
Pollina EA,
Borel C,
Zhang H,
Schmidt C,
Akeson EC,
Wenk MR,
Cimasoni L,
Arancio O,
Davisson MT,
Antonarakis SE,
Gardiner K,
De CP,
Di PG.
Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome. Proc Natl Acad Sci U S A 2008 Jul; 105(27):9415-20.