A restricted level of PQBP1 is needed for the best longevity of Drosophila.
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 receptorα/γ 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.
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Takuya
T
Tamura
Masaki
M
Sone
Yoko
Y
Nakamura
Teppei
T
Shimamura
Seiya
S
Imoto
Satoru
S
Miyano
Hitoshi
H
Okazawa
D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins; D004330:Drosophila; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007859:Learning Disabilities / Q000235:genetics; D008136:Longevity / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; C119246:PQBP1 protein, human