Ozkara Hatice Asuman
Department of Biochemistry, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey.
Brain Dev. 2004 Dec;26(8):497-505. doi: 10.1016/j.braindev.2004.01.005.
Sphingolipidoses are a subgroup of lysosomal storage diseases. They are defined as disorders caused by a genetic defect in catabolism of sphingosine-containing lipids. Catabolism of these lipids involves enzymes and activator proteins. After the discovery of lysosomes by de Duve and the demonstration of the first defective lysosomal enzyme by Hers in 1963, the first enzyme deficiency for sphingolipidoses was characterized in 1965 and all the defective enzymes were demonstrated in the last three decades. In 1984, the first activator protein was found and it expanded the concept of sphingolipidoses. In the following years, many researches have been undertaken to understand the molecular basis of these diseases, the mechanism of pathogenesis, the mechanism of lysosomal digestion of glycosphingolipids (GSLs) and the functional domains of lysosomal enzymes. New hypotheses and theories have been put forward for the mechanism of lysosomal digestion and pathogenesis. However, although much has been done, the pathogenesis of sphingolipidoses has not been fully elucidated. Mouse models of these diseases have facilitated the elucidation of pathogenesis and the development of therapeutic strategies for these diseases, which are not treatable at present except for Fabry and type 1 Gaucher disease. The purpose of this review is to collect information on the recent researches related to sphingolipidoses. The review includes the hydrolysis of GSLs in lysosome, mechanism of hydrolysis, pathogenesis and genetics of sphingolipidoses, a brief mouse model and therapeutic strategies of these diseases.
鞘脂贮积症是溶酶体贮积病的一个亚组。它们被定义为由含鞘氨醇脂质分解代谢中的遗传缺陷引起的疾病。这些脂质的分解代谢涉及酶和激活蛋白。在1955年德·迪夫发现溶酶体以及1963年赫斯证明第一种有缺陷的溶酶体酶之后，1965年确定了鞘脂贮积症的第一种酶缺乏症，并且在过去三十年中证明了所有有缺陷的酶。1984年，发现了第一种激活蛋白，这扩展了鞘脂贮积症的概念。在随后的几年里，人们进行了许多研究来了解这些疾病的分子基础、发病机制、糖鞘脂（GSLs）的溶酶体消化机制以及溶酶体酶的功能结构域。针对溶酶体消化和发病机制提出了新的假设和理论。然而，尽管已经做了很多工作，但鞘脂贮积症的发病机制尚未完全阐明。这些疾病的小鼠模型有助于阐明发病机制并开发针对这些疾病的治疗策略，目前除了法布里病和1型戈谢病外，这些疾病都无法治疗。本综述的目的是收集与鞘脂贮积症相关的最新研究信息。该综述包括溶酶体中GSLs的水解、水解机制、鞘脂贮积症的发病机制和遗传学、简要的小鼠模型以及这些疾病的治疗策略。
