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

Abstract

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)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)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)P 2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.Alzheimer's disease ͉ inositol 5-phosphatase ͉ phosphatidylinositol-4,5-bisphosphate ͉ phosphatidylinositol phosphate kinase ͉ synapse

Upregulation of threeDrosophilahomologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome

“…Note that co-overexpression of nla and synj together did not completely return PIP production to normal and that phosphoinositol 5Ј-phosphatase activity is still elevated compared to the control. This may explain why we only saw partial rescue of the satellite bouton phenotype, and this finding is consistent with a recent report that the phosphoinositol 5Ј-phosphatase activity is elevated in the brain of DS mouse model (40). What is the unique intracellular environment that leads to impaired vesicle recycling in the triple transgenic flies?…”

“…We did find an overall increase in the amount of synaptojanin protein in the brains of triple transgenic flies (as indicated by Western blot in Fig. S2) and at a level similar to those seen in DS mouse models and DS patient brain tissues (39,40). However, we discovered that dap160 overexpression creates differential synaptojanin distribution in subcellular regions of motor neurons where synaptojanin is increased in the cell body but normal at the synaptic terminal when synj is also coexpressed.…”

“…S1 and S2). It is important to note that the levels of intersectin1, synaptojanin1, and DSCR1 proteins have been shown to be elevated at a comparable amount in either human DS patient tissues or Ts65Dn mouse, a commonly used mouse DS model (ranging from Ϸ1.4-to 1.8-fold increases have been reported) (6,(39)(40)(41). Thus, our transgenic flies provide us a model system to investigate whether a dominant key gene or a subset of genes interact to affect phenotypes seen in DS.…”

Reduction of Synaptojanin 1 Accelerates Aβ Clearance and Attenuates Cognitive Deterioration in an Alzheimer Mouse Model

“…Synj1 has been linked to AD and Down's syndrome (5)(6)(7). It is a phosphatase that catalyzes the dephosphorylation of the signaling phospholipid PI(4,5)P 2 , which is shown to control clathrin-mediated endocytosis (40,41).…”

“…N2a cells were transfected with synj1 siRNA and maintained for 4 -5 days to achieve ϳ50 -80% knockdown of synj1 protein levels. Alternatively, cells were treated with a ␥-secretase inhibitor N-[N- (3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) (12,13) at 2 M overnight before further analysis. In some experiments, cells after siRNA treatment were incubated with a PIP 2 modulator (m-3-FBS or an inactive analog o-3-FBS) at 6.25 M overnight before further analysis.…”