title: The pathogenic human Torsin A in Drosophila activates the unfolded protein response and increases susceptibility to oxidative stress.
abstract: BACKGROUND
  Dystonia1 (DYT1) dystonia is caused by a glutamic acid deletion (ΔE) mutation in the gene encoding Torsin A in humans (HTorA). To investigate the unknown molecular and cellular mechanisms underlying DYT1 dystonia, we performed an unbiased proteomic analysis.
  
  
  RESULTS
  We found that the amount of proteins and transcripts of an Endoplasmic reticulum (ER) resident chaperone Heat shock protein cognate 3 (HSC3) and a mitochondria chaperone Heat Shock Protein 22 (HSP22) were significantly increased in the HTorA(ΔE)- expressing brains compared to the normal HTorA (HTorA(WT)) expressing brains. The physiological consequences included an increased susceptibility to oxidative and ER stress compared to normal HTorA(WT) flies. The alteration of transcripts of Inositol-requiring enzyme-1 (IRE1)-dependent spliced X box binding protein 1(Xbp1), several ER chaperones, a nucleotide exchange factor, Autophagy related protein 8b (ATG8b) and components of the ER associated degradation (ERAD) pathway and increased expression of the Xbp1-enhanced Green Fluorescence Protein (eGFP) in HTorA(ΔE) brains strongly indicated the activation of the unfolded protein response (UPR). In addition, perturbed expression of the UPR sensors and inducers in the HTorA(ΔE) Drosophila brains resulted in a significantly reduced life span of the flies. Furthermore, the types and quantities of proteins present in the anti-HSC3 positive microsomes in the HTorA(ΔE) brains were different from those of the HTorA(WT) brains.
  
  
  CONCLUSIONS
  Taken together, these data show that HTorA(ΔE) in Drosophila brains may activate the UPR and increase the expression of HSP22 to compensate for the toxic effects caused by HTorA(ΔE) in the brains.
authors.affiliation: ILSONG Institute of Life Science, Hallym University, 1605-4 Gwanyangdong, Dongan-gu, Anyang, Gyeonggido, 431-060, Republic of Korea. kilenay@daum.net.|Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Gangwon-do, 200-702, Republic of Korea. kilenay@daum.net.
authors.forename: A-Young
authors.initials: AY
authors.lastname: Kim
authors.affiliation: Korea Basic Science Institute, Sungbuk-gu, Seoul, 136-713, Republic of Korea. sjb@kbsi.re.kr.
authors.forename: Jong Bok
authors.initials: JB
authors.lastname: Seo
authors.affiliation: National Academy of Agricultural Science, Rural Development Administration, Suwon, 441-707, Republic of Korea. wtkim@korea.kr.
authors.forename: Won-Tae
authors.initials: WT
authors.lastname: Kim
authors.affiliation: ILSONG Institute of Life Science, Hallym University, 1605-4 Gwanyangdong, Dongan-gu, Anyang, Gyeonggido, 431-060, Republic of Korea. chj52@snu.ac.kr.|Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Gangwon-do, 200-702, Republic of Korea. chj52@snu.ac.kr.
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Korea Basic Science Institute, Sungbuk-gu, Seoul, 136-713, Republic of Korea. hl96022@daum.net.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology, Medical Biochemistry & Pathology, Université Laval, Québec, Qc, G1V 0A6, Canada. Genevieve.Morrow@fmed.ulaval.ca.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Morrow
authors.affiliation: Department of Molecular Biology, Medical Biochemistry & Pathology, Université Laval, Québec, Qc, G1V 0A6, Canada. robert.tanguay@ibis.ulaval.ca.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Tanguay
authors.affiliation: Howard Hughes Medical Institute, the Rockefeller University, New York, NY, 10065, USA. Hermann.Steller@rockefeller.edu.
authors.forename: Hermann
authors.initials: H
authors.lastname: Steller
authors.affiliation: ILSONG Institute of Life Science, Hallym University, 1605-4 Gwanyangdong, Dongan-gu, Anyang, Gyeonggido, 431-060, Republic of Korea. kohyh@hallym.ac.kr.|Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Gangwon-do, 200-702, Republic of Korea. kohyh@hallym.ac.kr.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Koh
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D018384:Oxidative Stress / Q000235:genetics; D053719:Tandem Mass Spectrometry; D056811:Unfolded Protein Response / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D051702:Activating Transcription Factor 6; D000730:Androstadienes; D037282:Calreticulin; D002867:Chromones; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006023:Glycoproteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C490752:Hsp22 protein, Drosophila; D018832:Molecular Chaperones; D009025:Morpholines; C108175:TOR1A protein, human; C517798:Xbp1 protein, Drosophila; C098410:glucose-regulated protein 170; D051701:Activating Transcription Factor 4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077191:Wortmannin