Elleder M
Institute of Inherited Metabolic Disorders, Charles University Prague, 1st Faculty of Medicine and University Hospital, Bldg. D, Division B, Ke Karlovu 2, 128 08, Prague 2, Czech Republic.
J Inherit Metab Dis. 2006 Dec;29(6):707-15. doi: 10.1007/s10545-006-0411-z. Epub 2006 Nov 2.
Gaucher disease (GD), deficiency of acid glucosylceramidase (GlcCer-ase) is characterized by deficient degradation of beta-glucosylceramide (GlcCer). It is well known that, in GD, the lysosomal accumulation of uncleaved GlcCer is limited to macrophages, which are gradually converted to storage cells with well known cytology--Gaucher cells (GCs). On the basis of previous studies of the disorder and of a comparison with other lysosomal enzymopathies affecting degradation of the GlcCer-based glycosphingolipid series, it is hypothesized that in other cell types (i.e. non-macrophage cells) the uncleaved GlcCer, in GlcCer-ase deficiency, is transferred to other cell compartments, where it may be processed and even accumulated to various degrees. The consequence of the abnormal extralysosomal load may differ according to the cell type and compartment targeted and may be influenced by genetically determined factors, by a number of acquired conditions, including the current metabolic situation. The sequelae of the uncleaved GlcCer extralysosomal transfer may range from probably innocent or positive stimulatory, to the much more serious, in which it interferes with a variety of cell functions, and in extreme cases, can lead to cell death. This alternative processing of uncleaved GlcCer may help to explain tissue alterations seen in GD that have, so far, resisted explanation based simply on the presence of GCs. Paralysosomal alternative processing may thus go a long way towards filling a long-standing gap in the understanding of the molecular pathology of the disorder. The impact of this alternative process will most likely be inversely proportional to the level of residual GlcCer-ase activity. Lysosomal sequestration of GlcCer in these cells is either absent or in those exceptional cases where it does occur, it is exceptional and rudimentary. It is suggested that paralysosomal alternative processing of uncleaved GlcCer is the main target for enzyme replacement therapy. The mechanism responsible for GlcCer transfer remains to be elucidated. It may also help in explaining the so far unclear origin of glucosylsphingosine (GlcSph) and define the mutual relation between these two processes.
戈谢病（GD）是一种由于酸性葡萄糖神经酰胺酶（GlcCer-ase）缺乏，导致β-葡萄糖神经酰胺（GlcCer）降解不足的疾病。众所周知，在戈谢病中，未裂解的GlcCer在溶酶体中的积累仅限于巨噬细胞，这些巨噬细胞会逐渐转变为具有特征性细胞学表现的储存细胞——戈谢细胞（GCs）。基于之前对该疾病的研究以及与其他影响基于GlcCer的糖鞘脂系列降解的溶酶体酶病的比较，有假说认为，在其他细胞类型（即非巨噬细胞）中，GlcCer-ase缺乏时未裂解的GlcCer会转移到其他细胞区室，在那里它可能会被加工，甚至不同程度地积累。异常的溶酶体外负荷的后果可能因靶向的细胞类型和区室而异，并可能受到遗传决定因素以及许多获得性条件的影响，包括当前的代谢状况。未裂解的GlcCer溶酶体外转移的后果可能从可能无害或具有积极刺激作用，到更为严重的情况，即干扰多种细胞功能，在极端情况下可导致细胞死亡。未裂解的GlcCer的这种替代加工方式可能有助于解释戈谢病中出现的组织改变，而迄今为止，仅基于戈谢细胞的存在无法对这些改变作出解释。因此，溶酶体外替代加工可能在很大程度上填补了对该疾病分子病理学理解方面长期存在的空白。这种替代过程的影响很可能与残余GlcCer-ase活性水平成反比。在这些细胞中，GlcCer的溶酶体隔离要么不存在，要么在极少数确实发生的情况下，也是罕见且基本的。有人提出，未裂解的GlcCer的溶酶体外替代加工是酶替代疗法的主要靶点。负责GlcCer转移的机制仍有待阐明。它也可能有助于解释迄今为止尚不清楚的葡萄糖神经鞘氨醇（GlcSph）的来源，并确定这两个过程之间的相互关系。
