title: A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome.
abstract: Expanded polyglutamine (polyQ) tract in the human TATA-box-binding protein (hTBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). To investigate the pathological effects of polyQ expansion, we established a SCA17 model in Drosophila. Similar to SCA17 patients, transgenic flies expressing a mutant hTBP protein with an expanded polyQ tract (hTBP80Q) exhibit progressive neurodegeneration, late-onset locomotor impairment and shortened lifespan. Microarray analysis reveals that hTBP80Q causes widespread and time-dependent transcriptional dysregulation in Drosophila. In a candidate screen for genetic modifiers, we identified RBP-J/Su(H), a transcription factor that contains Q/N-rich domains and participates in Notch signaling. Knockdown of Su(H) by RNAi further enhances hTBP80Q-induced eye defects, whereas overexpression of Su(H) suppresses such defects. While the Su(H) transcript level is not significantly altered in hTBP80Q-expressing flies, genes that contain Su(H)-binding sites are among those that are dysregulated. We further show that hTBP80Q interacts more efficiently with Su(H) than wild-type hTBP, suggesting that a reduction in the fraction of Su(H) available for its normal cellular functions contributes to hTBP80Q-induced phenotypes. While the Notch signaling pathway has been implicated in several neurological disorders, our study suggests a possibility that the activity of its nuclear component RBP-J/Su(H) may modulate the pathological progression in SCA17 patients.
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of Ministry of Education, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.forename: Minlu
authors.initials: M
authors.lastname: Zhang
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Deng
authors.forename: Junbo
authors.initials: J
authors.lastname: Liu
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Gordon
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Long J
authors.initials: LJ
authors.lastname: Lu
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D046228:Microarray Analysis; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism*; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D012097:Repressor Proteins; C088731:Su(H) protein, Drosophila; D035181:TATA-Box Binding Protein; C509817:TBP protein, human