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Title

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Authors
Voronov, S. V.
Frere, S. G.
Giovedi, Silvia
Pollina, E. A.
Schmidt, Cecilia
Akeson, E. C.
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Published in Proceedings of the National Academy of Sciences. 2008, vol. 105, no. 27, p. 9415-9420
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.
Keywords AnimalsBrain/enzymology/pathologyCognition Disorders/ enzymologyDisease Models, AnimalDown Syndrome/ enzymologyGene DosageHomeostasisLearningMaleMaze LearningMiceMice, Inbred C57BLMice, TransgenicNerve Tissue Proteins/genetics/ metabolismPhosphatidylinositol 4,5-Diphosphate/ metabolismPhosphoric Monoester Hydrolases/genetics/ metabolism
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PMID: 18591654
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VORONOV, S. V. et al. Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome. In: Proceedings of the National Academy of Sciences, 2008, vol. 105, n° 27, p. 9415-9420. https://archive-ouverte.unige.ch/unige:9078

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Deposited on : 2010-07-12

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