title: Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher's disease.
abstract: Gaucher's disease, the most common lysosomal storage disorder, is caused by the defective activity of glucocerebrosidase, the lysosomal hydrolase that degrades glucosylceramide. The neuronopathic forms of Gaucher's disease are characterized by severe neuronal loss, astrocytosis and microglial proliferation, but the cellular and molecular pathways causing these changes are not known. In the current study, we delineate the role of neuroinflammation in the pathogenesis of neuronopathic Gaucher's disease and show significant changes in levels of inflammatory mediators in the brain of a neuronopathic Gaucher's disease mouse model. Levels of messenger RNA expression of interleukin -1β, tumour necrosis factor-α, tumour necrosis factor-α receptor, macrophage colony-stimulating factor and transforming growth factor-β were elevated by up to ∼30-fold, with the time-course of the increase correlating with the progression of disease severity. The most significant elevation was detected for the chemokines CCL2, CCL3 and CCL5. Blood-brain barrier disruption was also evident in mice with neuronopathic Gaucher's disease. Finally, extensive elevation of nitrotyrosine, a hallmark of peroxynitrite (ONOO(-)) formation, was observed, consistent with oxidative damage caused by macrophage/microglia activation. Together, our results suggest a cytotoxic role for activated microglia in neuronopathic Gaucher's disease. We suggest that once a critical threshold of glucosylceramide storage is reached in neurons, a signalling cascade is triggered that activates microglia, which in turn releases inflammatory cytokines that amplify the inflammatory response, contributing to neuronal death.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Einat B
authors.initials: EB
authors.lastname: Vitner
authors.forename: Tamar
authors.initials: T
authors.lastname: Farfel-Becker
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.forename: Inbal
authors.initials: I
authors.lastname: Biton
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D042783:Endothelial Cells / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005776:Gaucher Disease / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005962:Glucosylceramidase / Q000172:deficiency; D007052:Ibuprofen / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D016385:TATA Box; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005962:Glucosylceramidase; D007052:Ibuprofen; D007074:Immunoglobulin G; D018799:Intercellular Adhesion Molecule-1; D007381:Intermediate Filament Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D014443:Tyrosine; D019010:Vascular Cell Adhesion Molecule-1; C491049:Aif1 protein, mouse; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C577484:NES protein, human; C577485:Nes protein, mouse; C002744:3-nitrotyrosine