title: The pathophysiology of GD - current understanding and rationale for existing and emerging therapeutic approaches.
abstract: 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.
authors.affiliation: Lysosomal Storage Disorders Unit, Royal Free Hospital, London, UK. d.hughes@medsch.ucl.ac.uk
authors.forename: Derralynn A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000502:physiology; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D056947:Enzyme Replacement Therapy; D005776:Gaucher Disease / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D015316:Genetic Therapy; D005962:Glucosylceramidase / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D005963:Glucosylceramides / Q000378:metabolism; D006017:Glycolipids / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D057165:Proteostasis Deficiencies / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy
chemical_list: D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D006017:Glycolipids; D017485:1-Deoxynojirimycin; C059896:miglustat; D005962:Glucosylceramidase; D002118:Calcium