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Tamura, T., Sone, M., Nakamura, Y., Shimamura, T., Imoto, S., Miyano, S., Okazawa, H. (2013). A restricted level of PQBP1 is needed for the best longevity of Drosophila.  Neurobiol. Aging 34(1): 356.e11--356.e20.
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A number of neurological diseases are caused by mutations of RNA metabolism-related genes. A complicating issue is that whether under- or overfunction of such genes is responsible for the phenotype. Polyglutamine tract binding protein-1, a causative gene for X-linked mental retardation, is also involved in RNA metabolism, and both mutation and duplication of the gene were reported in human patients. In this study, we first report a novel phenotype of dPQBP1 (drosophila homolog of Polyglutamine tract binding protein-1)-mutant flies, lifespan shortening. We next address the gene dose-phenotype relationship in lifespan shortening and in learning disability, a previously described phenotype. The 2 phenotypes are rescued by dPQBP1 but in different dose-phenotype relationships. Either insufficient or excessive expression of dPQBP1 does not recover lifespan, while excessive expression recovers learning ability. We finally address the mechanism of lifespan shortening. Tissue-specific expression of dPQBP1-RNA interference construct reveals both neural and nonneural dPQBP1 contribute to the lifespan, while the latter has a dominant effect. Gene expression profiling suggested retinophilin/MORN repeat containing 4, a gene promoting axonal degeneration, to contribute to lifespan shortening by neural dPQBP1. Systems biology analysis of the gene expression profiles revealed indirect influence of dPQBP1 on insulin-like growth factor 1, insulin receptor, and peroxisome proliferator-activated receptor╬▒/╬│ signaling pathways in nonneural tissues. Collectively, given that dPQBP1 affects multiple pathways in different dose-dependent and tissue-specific manners, dPQBP1 at a restricted expression level is needed for the best longevity.

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    Neurobiol. Aging
    Neurobiology of Aging
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