title: Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits.
abstract: Gaucher disease is caused by defective acid beta-glucosidase (GCase) function. Saposin C is a lysosomal protein needed for optimal GCase activity. To test the in vivo effects of saposin C on GCase, saposin C deficient mice (C-/-) were backcrossed to point mutated GCase (V394L/V394L) mice. The resultant mice (4L;C*) began to exhibit CNS abnormalities approximately 30 days: first as hindlimb paresis, then progressive tremor and ataxia. Death occurred approximately 48 days due to neurological deficits. Axonal degeneration was evident in brain stem, spinal cord and white matter of cerebellum accompanied by increasing infiltration of the brain stem, cortex and thalamus by CD68 positive microglial cells and activation of astrocytes. Electron microscopy showed inclusion bodies in neuronal processes and degenerating cells. Accumulation of p62 and Lamp2 were prominent in the brain suggesting the impairment of autophagosome/lysosome function. This phenotype was different from either V394L/V394L or C-/- alone. Relative to V394L/V394L mice, 4L;C* mice had diminished GCase protein and activity. Marked increases (20- to 30-fold) of glucosylsphingosine (GS) and moderate elevation (1.5- to 3-fold) of glucosylceramide (GC) were in 4L;C* brains. Visceral tissues had increases of GS and GC, but no storage cells were found. Neuronal cells in thick hippocampal slices from 4L;C* mice had significantly attenuated long-term potentiation, presumably resulting from substrate accumulation. The 4L;C* mouse mimics the CNS phenotype and biochemistry of some type 3 (neuronopathic) variants of Gaucher disease and is a unique model suitable for testing pharmacological chaperone and substrate reduction therapies, and investigating the mechanisms of neuronopathic Gaucher disease.
authors.affiliation: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Benjamin
authors.initials: B
authors.lastname: Liou
authors.forename: Huimin
authors.initials: H
authors.lastname: Ran
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Skelton
authors.forename: Michael T
authors.initials: MT
authors.lastname: Williams
authors.forename: Charles V
authors.initials: CV
authors.lastname: Vorhees
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kitatani
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: David P
authors.initials: DP
authors.lastname: Witte
authors.forename: You-Hai
authors.initials: YH
authors.lastname: Xu
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005962:Glucosylceramidase / Q000235:genetics*; D005963:Glucosylceramides / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D017774:Long-Term Potentiation / Q000502:physiology; D008136:Longevity; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism*; D009422:Nervous System Diseases / Q000150:complications* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011609:Psychosine / Q000031:analogs & derivatives* / Q000378:metabolism; D049231:Saposins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D005963:Glucosylceramides; D052119:Lysosomal-Associated Membrane Protein 2; D050505:Mutant Proteins; D049231:Saposins; D011609:Psychosine; C035742:sphingosyl beta-glucoside; D005962:Glucosylceramidase