TY - JOUR
T1 - Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome
AU - Voronov, Sergey V.
AU - Frere, Samuel G.
AU - Giovedi, Silvia
AU - Pollina, Elizabeth A.
AU - Borel, Christelle
AU - Zhang, Hong
AU - Schmidt, Cecilia
AU - Akeson, Ellen C.
AU - Wenk, Markus R.
AU - Cimasoni, Laurent
AU - Arancio, Ottavio
AU - Davisson, Muriel T.
AU - Antonarakis, Stylianos E.
AU - Gardiner, Katheleen
AU - De Camilli, Pietro
AU - Di Paolo, Gilbert
PY - 2008/7/8
Y1 - 2008/7/8
N2 - Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P2 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)P2 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)P2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.
AB - Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P2 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)P2 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)P2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.
KW - Alzheimer's disease
KW - Inositol 5-phosphatase
KW - Phosphatidylinositol phosphate kinase
KW - Phosphatidylinositol-4,5- bisphosphate
KW - Synapse
UR - https://www.scopus.com/pages/publications/48249116002
U2 - 10.1073/pnas.0803756105
DO - 10.1073/pnas.0803756105
M3 - Article
C2 - 18591654
AN - SCOPUS:48249116002
SN - 0027-8424
VL - 105
SP - 9415
EP - 9420
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
ER -