Role of Phosphoinositide Imbalance in Down Syndrome

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DESCRIPTION (provided by applicant): Down syndrome (DS) is the most common cause of mental retardation (MR). In DS, integrated gene expression is altered due to the presence of a third copy of chromosome 21 (HC21), which results in the overexpression of the trisomic genes. Although MR has been linked to non-overlapping regions of HC21, indicating the multigenicity of its etiology, the relative contribution of single genes to this phenotype is unknown. Here we propose that SYNJ1 is a strong candidate for contributions to MR in DS. SYNJ1 encodes synaptojanin 1, a brain- enriched phosphoinositide phosphatase that negatively regulates the levels of phosphatidylinositol-4,5-bisphosphate (PIP2). This lipid has pleiotropic roles in cells, such as signaling, organelle trafficking and actin dynamics. In nerve terminals, PIP2 regulates synaptic vesicle trafficking, due to its ability to recruit to the plasmalemma key components of the exocytic and endocytic machineries. Our genetic studies in mouse have recently provided robust evidence for a role of synaptojanin 1 in synaptic vesicle recycling, a process that involves clathrin-mediated endocytosis. Moreover, we have found that the lack of the main PIP2-synthesizing enzyme in the brain also impairs synaptic vesicle trafficking. Interestingly, our preliminary work on a mouse model of partial trisomy 21 (Ts65Dn) has shown lower PI(4,5)P2 levels in the brain of these animals. Therefore, we hypothesize that the imbalance of PIP2 metabolism caused by the overexpression of SYNJ1 produces synaptic vesicle trafficking defects in DS. We also hypothesize that these defects may contribute to deficits of higher brain functions, such as MR. To test these hypotheses, we will study PIP2 metabolism, synaptic vesicle trafficking and learning performances in partial trisomy mice and assess potential ameliorations of the phenotypes after restoring to disomy the SYNJ1 gene in Ts65Dn mice using SYNJ1 knockout mice. Finally, we will characterize mice overexpressing SYNJ1 to test whether gene dosage imbalance for SYNJ1 alone recapitulates any of the phenotypes observed in Ts65Dn mice.