title: Neurodegeneration caused by polyglutamine expansion is regulated by P-glycoprotein in Drosophila melanogaster.
abstract: Trinucleotide CAG repeat disorders are caused by expansion of polyglutamine (polyQ) domains in certain proteins leading to fatal neurodegenerative disorders and are characterized by accumulation of inclusion bodies in the neurons. Clearance of these inclusion bodies holds the key to improve the disease phenotypes, which affects basic cellular processes such as transcription, protein degradation and cell signaling. In the present study, we show that P-glycoprotein (P-gp), originally identified as a causative agent of multidrug-resistant cancer cells, plays an important role in ameliorating the disease phenotype. Using a Drosophila transgenic strain that expresses a stretch of 127 glutamine repeats, we demonstrate that enhancing P-gp levels reduces eye degeneration caused by expression of polyQ, whereas reducing it increases the severity of the disease. Increase in polyQ inclusion bodies represses the expression of mdr genes, suggesting a functional link between P-gp and polyQ. P-gp up-regulation restores the defects in the actin organization and precise array of the neuronal connections caused by inclusion bodies. β-Catenin homolog, Armadillo, also interacts with P-gp and regulates the accumulation of inclusion bodies. These results thus show that P-gp and polyQ interact with each other, and changing P-gp levels can directly affect neurodegeneration.
authors.affiliation: Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Yadav
authors.forename: Madhu G
authors.initials: MG
authors.lastname: Tapadia
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism*; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D017344:Genes, Insect; D019450:Genes, MDR; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D029721:Drosophila Proteins; D010455:Peptides; C097188:polyglutamine; D014700:Verapamil
keywords: P-glycoprotein; neurodegeneration; polyQ inclusion bodies; β-catenin/Armadillo
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