title: Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila.
abstract: Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of a polyglutamine [poly(Q)] repeat within the androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment of the human AR protein. Expression of a pathogenic AR protein with an expanded poly(Q) repeat in Drosophila results in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. We have studied the influence of ubiquitin-dependent modification and the proteasome pathway on neural degeneration and AR protein fragment solubility. Compromising the ubiquitin/proteasome pathway enhances degeneration and decreases poly(Q) protein solubility. Our data further suggest that Hsp70 and the proteasome act in an additive manner to modulate neurodegeneration. Through the over-expression of a mutant of the SUMO-1 activating enzyme Uba2, we further show that poly(Q)-induced degeneration is intensified when the cellular SUMO-1 protein conjugation pathway is altered. These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: H Y Edwin
authors.initials: HY
authors.lastname: Chan
authors.forename: John M
authors.initials: JM
authors.lastname: Warrick
authors.forename: Isabella
authors.initials: I
authors.lastname: Andriola
authors.forename: Diane
authors.initials: D
authors.lastname: Merry
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D017353:Gene Deletion; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D020966:Muscular Disorders, Atrophic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010455:Peptides / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics; D025842:SUMO-1 Protein / Q000502:physiology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000494:pharmacology; D044764:Ubiquitin-Activating Enzymes
chemical_list: D018840:HSP70 Heat-Shock Proteins; D009097:Multienzyme Complexes; D010455:Peptides; D011506:Proteins; D011944:Receptors, Androgen; D025842:SUMO-1 Protein; D025841:Small Ubiquitin-Related Modifier Proteins; C470301:UBA2 protein, human; D025801:Ubiquitin; C097188:polyglutamine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes