期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：50
页码：21665-21670
DOI：10.1073/pnas.1014376107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
