title: Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis.
abstract: Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNF alpha), transforming growth factor (TGF beta 1) and interleukin 1 beta (IL1 beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses.
authors.affiliation: Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jeyakumar
authors.forename: R
authors.initials: R
authors.lastname: Thomas
authors.forename: E
authors.initials: E
authors.lastname: Elliot-Smith
authors.forename: D A
authors.initials: DA
authors.lastname: Smith
authors.forename: A C
authors.initials: AC
authors.lastname: van der Spoel
authors.forename: A
authors.initials: A
authors.lastname: d'Azzo
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
authors.forename: T D
authors.initials: TD
authors.lastname: Butters
authors.forename: R A
authors.initials: RA
authors.lastname: Dwek
authors.forename: F M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D001812:Blood-Brain Barrier; D016207:Cytokines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005733:Gangliosidoses / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D020143:Gangliosidoses, GM2 / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D016537:Gangliosidosis, GM1 / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D005802:Genes, MHC Class II / Q000502:physiology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D051379:Mice; D012497:Sandhoff Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D013661:Tay-Sachs Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat