title: Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl.
abstract: Gaucher disease (GD), the most common lysosomal storage disorder of humans, is caused by mutations in the gene coding for the enzyme glucocerebrosidase (GCase). Clinical manifestations vary among patients with the three types of GD, and phenotypic heterogeneity occurs even among patients with identical mutations. To gain insight into why phenotypic heterogeneity occurs in GD, we investigated mechanisms underlying the net loss of GCase catalytic activity in cultured skin fibroblasts derived from patients with the three types of GD. The findings indicate that the loss of catalytic activity of GCase correlates with its quantitative reduction, rather than a decrease in functional capacity of mutant enzyme. Use of a proteasome inhibitor, lactacystin, resulted in increased expression of GCase, suggesting a mechanism of protein degradation in GD. Furthermore, reduced binding of GCase to TCP1 ring complex (TRiC), a regulator of correct protein folding, may result in defective maturation of nascent GCase in GD cells. Additionally, increased interaction between GCase and c-Cbl, an E3 ubiquitin ligase, may be involved in the degradation and loss of GCase in GD. The findings suggest that specific molecular mediators involved in GCase maturation and degradation could be responsible for phenotypic variation among patients with the same genotypes and that these mediators could be therapeutically targeted to increase GCase activity in patients with GD.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chiang
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Iyer
authors.forename: Eli
authors.initials: E
authors.lastname: Thompson
authors.forename: Christine R
authors.initials: CR
authors.lastname: Kaneski
authors.forename: David S
authors.initials: DS
authors.lastname: Xu
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Masako
authors.initials: M
authors.lastname: Chen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hodes
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D056404:Chaperonin Containing TCP-1 / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics; D005962:Glucosylceramidase / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; C533304:TCP1 protein, human; C067713:lactacystin; D050721:Proto-Oncogene Proteins c-cbl; D005962:Glucosylceramidase; D046988:Proteasome Endopeptidase Complex; D056404:Chaperonin Containing TCP-1; C067419:CBL protein, human; D000111:Acetylcysteine