title: Molecular chaperones affect GTP cyclohydrolase I mutations in dopa-responsive dystonia.
abstract: Unstable GTP cyclohydrolase I (GCH) mutations in dopa-responsive dystonia (DRD) can exert a dominant-negative effect in the HeLa cell model, but in a batch of cells this effect could not be shown. Through differential display, we found a higher Hsc70 expression in the non-dominant-negative cells. We further demonstrated that ectopic expression of Hsp40/Hsp70 stabilized the GCH mutant G201E. Moreover, Hsp90 inhibitor geldanamycin destroyed the wild-type GCH level, and heat shock increased the synthesis of GCH protein. Therefore, the dominant-negative effect produced by unstable proteins would be susceptible to the status of molecular chaperones, which could be the modifying genes and therapeutic targets for DRD and other genetic diseases.
authors.affiliation: Department of Pediatrics and Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taiwan.
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Lu
authors.forename: Kuo-Yuan
authors.initials: KY
authors.lastname: Hwa
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Fan
authors.forename: Yu-May
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016227:Benzoquinones; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D006224:Cricetinae; D004252:DNA Mutational Analysis; D004421:Dystonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000235:genetics; D005998:Glycine / Q000235:genetics; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D007980:Levodopa; D018832:Molecular Chaperones / Q000502:physiology*; D009154:Mutation; D011506:Proteins / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D016227:Benzoquinones; C494647:DNAJB1 protein, human; D004791:Enzyme Inhibitors; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011506:Proteins; D011809:Quinones; D012333:RNA, Messenger; D018698:Glutamic Acid; D007980:Levodopa; D006136:GTP Cyclohydrolase; D005998:Glycine; C001277:geldanamycin