Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data

Abstract

SummaryGaucher 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.

Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage

“…However, poorly responsive variants of GD1, such as cancers, Parkinson disease, hepatocellular disease, and osteoporosis, have emerged. This clinical complexity seen with a single gene defect, in essence, underscores our limited understanding of the multiple cell types and pathways that are likely involved in the pathogenesis of GD1 (17). Here, we report that a mouse in which the GBA1 gene was deleted conditionally using an Mx1 promoter recapitulated the human disease almost in its entirety.…”

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

“…Our findings will permit a more thorough assessment of the potential role of GBA2 in Gaucher disease, especially because, in Gaucher cells, the accumulation of GlcCer appears not to be limited to the endolysosomal compartment (93). Aureli et al (85) and Burke et al (86) recently reported that the GBA2 activity is increased in Gaucher fibroblasts and leukocytes and in GBA-deficient mouse brains, and Körschen et al (11) found that the GBA2 activity is reduced in murine GBA-deficient fibroblasts and in type 2 Gaucher fibroblasts.…”

Gaucher disease geneGBAfunctions in immune regulation

“…Increasing clinical evidence suggests that the pathophysiology of classic GD is more complex and involves system-wide dysfunction of cell types other than macrophages (3)(4)(5). The involvement of immune cells has been implicated, but the underlying molecular defect is poorly understood (6)(7)(8)(9).…”