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Molecular chaperones affect GTP cyclohydrolase I mutations in dopa‐responsive dystonia
Author(s) -
Hwu WuhLiang,
Lu MeiYi,
Hwa KuoYuan,
Fan ShuWen,
Lee YuMay
Publication year - 2004
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20122
Subject(s) - gtp cyclohydrolase i , geldanamycin , mutant , heat shock protein , hsp90 , mutation , dystonia , biology , ectopic expression , gtp' , gene , microbiology and biotechnology , genetics , biochemistry , tetrahydrobiopterin , neuroscience , enzyme , cofactor
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. Ann Neurol 2004;55:875–878