Zusammenfassung
Morbus Gaucher ist eine genetische Erkrankung des Sphingolipidstoffwechsels, die durch eine Fehlfunktion des lysosomalen membranassoziierten Glykoproteins Glucozerebrosidase hervorgerufen wird. Die Folgen sind eine intrazelluläre Speicherung von Glukosylzeramid und anderen Glukolipiden. Obwohl der Gendefekt und die relevanten biochemischen Veränderungen bei GD bekannt sind, werden alle Mechanismen, die zu den Erkrankungsmanifestationen führen, bislang noch nicht vollständig verstanden. Die progressive Zunahme von Speicherzellen erklärt zwar einige der Erkrankungsmanifestationen, jedoch die gesamte Pathologie der Erkrankung scheint von komplexerer Natur mit einem Einfluß des gespeicherten Materials auf diverse intra-und ertrazelluläre Funktionen zu sein. Im folgenden Artikel wird das Glukozerebrosidase-Gen und sein Proteinprodukt zu verschiedenen metabolischen Gesichtspunkten betrachtet und damit im Zusammenhang die aktuell verfügbaren bzw. in Entwicklung befindlichen therapeutischen Ansätze und deren Wirkungsweisen auf die pathologischen Abläufe bei GD analysiert.
Summary
Gaucher disease is a genetic disorder of sphingolipid metabolism resulting from dysfunction of the lysosomal membrane-associated glycoprotein glucocerebrosidase (GBA) and resulting in intracellular accumulation of glucosylceramide and other glycolipids. Although the gene defect and relevant biochemical pathways have been defined, the mechanisms by which substrate accumulation causes disease manifestations are not well understood. The direct effects of a build up of substrate laden cells may account for some aspects of disease but the overall pathology is likely to be more complex with effects of stored material on a variety of intra and extra cellular functions. In this article we review the GBA gene and its protein product, with associated defects, lipid metabolism and storage, enzyme misfolding and endoplasmic reticulum stress, calcium homeostasis, oxidative stress and autophagy and at each point examine how therapies that are currently available, in clinical development or at earlier stages of basic research might address the pathological mechanisms.
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Hughes, D., Pastores, G. The pathophysiology of GD – current understanding and rationale for existing and emerging therapeutic approaches. Wien Med Wochenschr 160, 594–599 (2010). https://doi.org/10.1007/s10354-010-0864-4
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DOI: https://doi.org/10.1007/s10354-010-0864-4
Schlüsselwörter
- Morbus Gaucher
- Glukozerebrosidase
- Lysosomale Speichererkrankung
- Pathophysiologie
- Enzymersatztherapie
- Substratreduktionstherapie
- Chaperone