Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21665-70. doi: 10.1073/pnas.1014376107. Epub 2010 Nov 22.
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.
戈谢病（GD）是人类最常见的溶酶体贮积症，由编码葡萄糖脑苷脂酶（GCase）的基因突变引起。三种类型的 GD 患者的临床表现各不相同，即使是具有相同突变的患者也会出现表型异质性。为了深入了解 GD 中表型异质性发生的原因，我们研究了三种类型 GD 患者来源的培养皮肤成纤维细胞中 GCase 催化活性净损失的潜在机制。研究结果表明，GCase 催化活性的丧失与其定量减少相关，而不是与突变酶的功能能力下降相关。使用蛋白酶体抑制剂乳胞素可导致 GCase 的表达增加，表明 GD 中存在蛋白质降解机制。此外，GCase 与 TCP1 环复合物（TRiC）的结合减少，TRiC 是一种正确折叠蛋白的调节剂，这可能导致 GD 细胞中新生 GCase 的成熟缺陷。此外，GCase 与 c-Cbl（一种 E3 泛素连接酶）之间的相互作用增加可能与 GD 中 GCase 的降解和丢失有关。这些发现表明，参与 GCase 成熟和降解的特定分子介质可能是导致相同基因型患者表型变异的原因，并且这些介质可以作为治疗靶点，以增加 GD 患者的 GCase 活性。
