Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease.
Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease.
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DOI：
10.1042/bst0381453
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发表时间：
2010-12
影响因子：
3.9
通讯作者：
Bonten E
中科院分区：
文献类型：
--
作者：
d'Azzo A;Bonten E
溶酶体系统包括对细胞组分的分选、消化、再循环和分泌至关重要的细胞器的专门网络。溶酶体通过其水解酶的含量调节通过生物合成或内吞途径到达这些细胞器的大量底物的降解。影响这些水解酶中的一种或多种的基因缺陷导致溶酶体贮积病（LSD）。这强调了这些酶明显缺乏冗余以及溶酶体系统在细胞和组织稳态中的重要性。一些溶酶体酶可以形成多蛋白复合物，其通常协同作用于底物，并且在这种构型中，可以更有效地响应底物负荷和组成的变化。一种充分表征的溶酶体多酶复合物是由糖苷酶、β-半乳糖苷酶（β-GAL）和神经酰胺酶-1（NEU 1）以及丝氨酸羧肽酶保护蛋白/组织蛋白酶A（PPCA）组成的复合物。三种神经退行性LSD是由这些溶酶体酶的单一或联合缺乏引起的。唾液酸沉积症（NEU 1缺乏症）和半乳糖唾液酸沉积症（NEU 1和β-gal缺乏症的组合，继发于PPCA的原发性缺陷）属于糖蛋白储存疾病，而GM 1-神经节苷脂沉积症（β-GAL缺乏症）是鞘糖脂储存疾病。由于酶活性丧失和/或特定代谢物在各种细胞类型中积累而被解除调节的新分子途径的鉴定揭示了疾病发病机制，并可能为未来开发这些LSD的新疗法铺平道路。
The lysosomal system comprises a specialized network of organelles crucial for the sorting, digestion, recycling and secretion of cellular components. With their content of hydrolytic enzymes lysosomes regulate the degradation of a multitude of substrates that reach these organelles via the biosynthetic or the endocytic route. Gene defects that affect one or more of these hydrolases lead to lysosomal storage diseases (LSD). This underscores the apparent lack of redundancy of these enzymes and the importance of the lysosomal system in cell and tissue homeostasis. Some of the lysosomal enzymes may form multiprotein complexes, which usually work synergistically on substrates and in this configuration, may respond more efficiently to changes in substrate load and composition. A well-characterized lysosomal multienzyme complex is the one comprised of the glycosidases, β-galactosidase (β-GAL) and neuramidase-1 (NEU1), and of the serine carboxypeptidase protective protein/cathepsin A (PPCA). Three neurodegenerative LSDs are caused by either single or combined deficiency of these lysosomal enzymes. Sialidosis (NEU1 deficiency) and galactosialidosis (combined NEU1 and β-gal deficiency, secondary to a primary defect of PPCA) belong to the glycoprotein storage diseases, whereas GM1-gangliosidosis (β-GAL deficiency) is a glycosphingolipid storage disease. Identification of novel molecular pathways that are deregulated because of loss of enzyme activity and/or accumulation of specific metabolites in various cell types has shed light on mechanisms of disease pathogenesis and may pave the way for future development of new therapies for these LSDs.