title: Deactivation of TBP contributes to SCA17 pathogenesis.
abstract: Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by the expansion of polyglutamine (polyQ) within the TATA box-binding protein (TBP). Previous studies have shown that polyQ-expanded TBP forms neurotoxic aggregates and alters downstream genes. However, how expanded polyQ tracts affect the function of TBP and the link between dysfunctional TBP and SCA17 is not clearly understood. In this study, we generated novel Drosophila models for SCA17 that recapitulate pathological features such as aggregate formation, mobility defects and premature death. In addition to forming neurotoxic aggregates, we determined that polyQ-expanded TBP reduces its own intrinsic DNA-binding and transcription abilities. Dysfunctional TBP also disrupts normal TBP function. Furthermore, heterozygous dTbp amorph mutant flies exhibited SCA17-like phenotypes and flies expressing polyQ-expanded TBP exhibited enhanced retinal degeneration, suggesting that loss of TBP function may contribute to SCA17 pathogenesis. We further determined that the downregulation of TBP activity enhances retinal degeneration in SCA3 and Huntington's disease fly models, indicating that the deactivation of TBP is likely to play a common role in polyQ-induced neurodegeneration.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Tun-Chieh
authors.initials: TC
authors.lastname: Hsu
authors.affiliation: Department of Laboratory Medicine, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 35664, Taiwan and.
authors.forename: Cheng-Kuang
authors.initials: CK
authors.lastname: Wang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lee
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Hsiu-Mei
authors.initials: HM
authors.lastname: Hsieh-Li
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, College of Medicine, Chang-Gung University, Taoyuan 33305, Taiwan.
authors.forename: Long-Sun
authors.initials: LS
authors.lastname: Ro
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, College of Medicine, Chang-Gung University, Taoyuan 33305, Taiwan.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan mtsu@ntnu.edu.tw.
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Su
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008136:Longevity / Q000235:genetics; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D066329:Protein Aggregates; D011485:Protein Binding; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035181:TATA-Box Binding Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D010455:Peptides; D066329:Protein Aggregates; D035181:TATA-Box Binding Protein; C097188:polyglutamine