title: Enhanced calcium release in the acute neuronopathic form of Gaucher disease.
abstract: Gaucher disease is an inherited metabolic disorder caused by defective activity of the lysosomal enzyme, glucocerebrosidase, resulting in accumulation of the lipids, glucosylceramide (GlcCer), and glucosylsphingosine (GlcSph). Little is known about the mechanism leading from lipid accumulation to disease, particularly in the acute and subacute neuronopathic forms of Gaucher disease, types 2 and 3, respectively. Recent work from our laboratory has shown, in animal models, that GlcCer enhances agonist-induced calcium release from intracellular stores via the ryanodine receptor, which results in neuronal cell death. We now test whether calcium release is altered in human brain tissue obtained post-mortem from Gaucher disease patients. Agonist-induced calcium release via the ryanodine receptor was significantly enhanced (P < 0.05) in brain microsomes from the acute neuronopathic form of Gaucher disease (type 2) (43 +/- 6% of the calcium in microsomes) compared to the subacute (type 3) (27 +/- 3%) and the non-neuronopathic (type 1) (28 +/- 6%) forms, and controls (18 +/- 3%), and correlated with levels of GlcCer accumulation. These findings suggest that defective calcium homeostasis may be a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease, and may potentially offer new therapeutic approaches for disease management.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dori
authors.initials: D
authors.lastname: Pelled
authors.forename: Selena
authors.initials: S
authors.lastname: Trajkovic-Bodennec
authors.forename: Emyr
authors.initials: E
authors.lastname: Lloyd-Evans
authors.forename: Ellen
authors.initials: E
authors.lastname: Sidransky
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020013:Calcium Signaling / Q000235:genetics*; D002675:Child, Preschool; D005776:Gaucher Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism; D008875:Middle Aged; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D002120:Calcium Channel Agonists; D005963:Glucosylceramides; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium