title: Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome.
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.
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Voronov
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Frere
authors.forename: Silvia
authors.initials: S
authors.lastname: Giovedi
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Pollina
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Cecilia
authors.initials: C
authors.lastname: Schmidt
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Akeson
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Laurent
authors.initials: L
authors.lastname: Cimasoni
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Muriel T
authors.initials: MT
authors.lastname: Davisson
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Katheleen
authors.initials: K
authors.lastname: Gardiner
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D003072:Cognition Disorders / Q000201:enzymology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000201:enzymology*; D018628:Gene Dosage; D006706:Homeostasis; D007858:Learning; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C097702:synaptojanin