title: A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease.
abstract: Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis.
authors.affiliation: Biochemistry I, Department of Chemistry, Bielefeld University, Bielefeld D-33615, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Wolf
authors.affiliation: Biochemical Institute, University of Kiel, Kiel D-24098, Germany.
authors.forename: Markus
authors.identifier: 0000-0002-9699-9351
authors.initials: M
authors.lastname: Damme
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Department of Biochemistry and Pharmacology, Centre for Clinical Proteomics, Odense University Hospital, Odense DK-5000, Denmark.
authors.forename: Hans Christian
authors.identifier: 0000-0002-7763-3637
authors.initials: HC
authors.lastname: Beck
authors.affiliation: ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany.
authors.forename: Irm
authors.initials: I
authors.lastname: Hermans-Borgmeyer
authors.affiliation: Department of Anatomy, University of Kiel, Kiel D-24098, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Biochemistry I, Department of Chemistry, Bielefeld University, Bielefeld D-33615, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dierks
authors.affiliation: Biochemistry I, Department of Chemistry, Bielefeld University, Bielefeld D-33615, Germany torben.luebke@uni-bielefeld.de.
authors.forename: Torben
authors.initials: T
authors.lastname: Lübke
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005643:Fucose / Q000378:metabolism; D005645:Fucosidosis / Q000378:metabolism* / Q000473:pathology* / Q000652:urine; D005678:G(M2) Ganglioside / Q000378:metabolism; D006001:Glycoconjugates / Q000652:urine; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008247:Lysosomes / Q000201:enzymology / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D059748:Proteolysis; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D014781:Viscera / Q000378:metabolism / Q000473:pathology; D005644:alpha-L-Fucosidase / Q000172:deficiency / Q000378:metabolism
chemical_list: D006001:Glycoconjugates; D006023:Glycoproteins; D005678:G(M2) Ganglioside; D005643:Fucose; D005644:alpha-L-Fucosidase
keywords: Fucosidosis; Lysosomal storage disorder; Neurodegeneration