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J Inherit Metab Dis. 2006 Dec;29(6):707-15. Epub 2006 Nov 2.

Glucosylceramide transfer from lysosomes--the missing link in molecular pathology of glucosylceramidase deficiency: a hypothesis based on existing data.

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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.


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.

[Indexed for MEDLINE]

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