Role of PIP2 metabolism imbalance in Down Syndrome

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DESCRIPTION (provided by applicant): Down syndrome (DS) is the most common cause of mental retardation. In DS, integrated gene expression is altered due to the presence of a third copy of human chromosome 21 (HC21). Although mental retardation 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 mental retardation in DS. Synj1 encodes synaptojanin 1, a brain- enriched lipid phosphatase that dephosphorylates PIP2. This plasma membrane-enriched lipid regulates many processes, including signal transduction, membrane trafficking and ion channel function. Our previous work has shown that PIP2 regulates synaptic vesicle (SV) trafficking and thereby, neurotransmission. This property is largely due to the ability of this lipid to recruit to the plasma membrane key components of the endocytic machinery, which mediates the recycling of SVs. More recently, our studies have revealed that PIP2 metabolism is altered in the brain of Ts65Dn mice, the major genetic model of Down syndrome. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and it is recapitulated in transgenic mice overexpressing Synj1 from a genomic (BAC) construct [Tg(Synj1)]. Primary cortical neurons derived from Tg(Synj1) mice show defects in SV trafficking that are reminiscent of those found in neurons lacking a major PIP2-synthesizing enzyme. Additionally, Tg(Synj1) mice exhibit deficits in performance of the Morris water maze, suggesting that PIP2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in genetic models of DS. Based on our preliminary studies, the main goals of this proposal will be (i) to further characterize PIP2 metabolism defects in intact synaptosomes and in cultured neurons from the cortex of DS mouse models as well as of human embryos with DS; (ii) to further characterize physiologic and ultrastructural defects in synapses from Ts65Dn and Tg(Synj1) neurons; and (iii) to further explore the impact of PIP2 deficiency on the learning ability of transgenic mice in the Morris water maze paradigm as well as in other behavioral tasks. The discovery of specific phenotypes will prompt us to assess whether restoring Synj1 to disomy in the Ts65Dn background ameliorates these defects. We anticipate that our studies will identify gene dosage imbalance for Synj1 as a key factor in brain dysfunction occurring in genetic models of DS and provide a better understanding of the molecular basis underlying neurophysiological deficits and mental retardation in DS. PUBLIC HEALTH RELEVANCE: Down syndrome is the most common cause of mental retardation. The main goal of our proposed research is to further characterize the implication of a gene, SYNJ1, in neurophysiological and behavioral deficits in various mouse models of this disorder. This proposal builds on our own evidence showing that the trisomy of SYNJ1 causes a biochemical defect, i.e. the deficiency of a regulatory lipid called PIP2, and learning deficits in a transgenic mouse model.