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: Sergey V Voronov, Samuel G Frere, Silvia Giovedi, Elizabeth A Pollina, Christelle Borel, Hong Zhang, Cecilia Schmidt, Ellen C Akeson, Markus R Wenk, Laurent Cimasoni, Ottavio Arancio, Muriel T Davisson, Stylianos E Antonarakis, Katheleen Gardiner, Pietro De Camilli, Gilbert Di Paolo
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 27 Pg. 9415-20 (Jul 08 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18591654 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Phosphatidylinositol 4,5-Diphosphate
• synaptojanin
• Phosphoric Monoester Hydrolases
• phosphoinositide 5-phosphatase

Topics

• Animals
• Brain (enzymology, pathology)
• Cognition Disorders (enzymology)
• Disease Models, Animal
• Down Syndrome (enzymology)
• Gene Dosage
• Homeostasis
• Learning
• Male
• Maze Learning
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Tissue Proteins (genetics, metabolism)
• Phosphatidylinositol 4,5-Diphosphate (metabolism)
• Phosphoric Monoester Hydrolases (genetics, metabolism)