title: Critical role of iron in the pathogenesis of the murine gangliosidoses.
abstract: Neurodegeneration is a prominent feature of the gangliosidoses, a group of lysosomal storage diseases. Here we show altered iron homeostasis in mouse models of both GM1 and GM2 gangliosidoses, which are characterized by progressive depletion of iron in brain tissue. This finding contrasts with the findings in many other neurological disorders, where excess iron deposition has been reported. We found that key regulators of iron homeostasis, hepcidin and IL-6, were increased in gangliosidoses mice. In the brain, the principal iron transport and delivery protein transferrin was reduced, accompanied by a progressive inability of the brain to acquire iron from the circulation. Expression of the transferrin receptor was up-regulated reciprocally. Despite the deregulation of iron homeostasis administration of iron prolonged survival in the diseased mice by up to 38%, with onset of disease delayed and motor function preserved.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford 0X1 3QT, UK. mylvaganam.jeyakumar@pharm.ox.ac.uk
authors.forename: Mylvaganam
authors.initials: M
authors.lastname: Jeyakumar
authors.forename: Ian
authors.initials: I
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D017668:Age of Onset; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001774:Blood Chemical Analysis; D001921:Brain / Q000503:physiopathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D020143:Gangliosidoses, GM2 / Q000178:diet therapy / Q000401:mortality / Q000503:physiopathology*; D016537:Gangliosidosis, GM1 / Q000178:diet therapy / Q000401:mortality / Q000503:physiopathology*; D064451:Hepcidins; D054819:Hexosaminidase B / Q000235:genetics; D006706:Homeostasis; D015850:Interleukin-6 / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D009043:Motor Activity / Q000502:physiology; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D016896:Treatment Outcome; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron; D001616:beta-Galactosidase; D054819:Hexosaminidase B