Molecular chaperones affect GTP cyclohydrolase I mutations in dopa-responsive dystonia
Journal
Annals of Neurology
Journal Volume
55
Journal Issue
6
Pages
875-878
Date Issued
2004
Author(s)
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.
SDGs
Other Subjects
chaperone; DOPA; geldanamycin; guanosine triphosphate cyclohydrolase I; heat shock cognate protein 70; heat shock protein 40; heat shock protein 70; heat shock protein 90; mutant protein; protein inhibitor; article; controlled study; differential display; dominant inheritance; dominant negative effect; dopa responsive dystonia; dystonia; gene expression; gene mutation; genetic disorder; heat shock; HeLa cell; human; human cell; priority journal; protein synthesis; Animals; Animals, Newborn; Benzoquinones; Blotting, Northern; Blotting, Western; Cell Line; Cricetinae; DNA Mutational Analysis; Dystonia; Embryo; Enzyme Inhibitors; Gene Expression Regulation; Glutamic Acid; Glycine; GTP Cyclohydrolase; Heat-Shock Proteins; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Levodopa; Molecular Chaperones; Mutation; Proteins; Quinones; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Transfection
Type
journal article