Characterization of a C57BL/6 congenic mouse strain of mucopolysaccharidosis type IIIA

Crawley, Allison C.; Gliddon, Briony L.; Auclair, Dyane; Brodie, Suzanne L.; Hirte, Craig; King, Barbara; Fuller, Maria; Hemsley, Kim M.; Hopwood, John J.

doi:10.1016/j.brainres.2006.05.079

Cited by 95 publications

(123 citation statements)

References 31 publications

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“…The age of onset of particular behavioral deficits varies among different LSD mouse models, and can be affected by strain background. Similar onset of impaired learning and memory in Morris water maze was observed in MPS IIIB (Crawley et al, 2006), however, earlier manifestation was detected in male affected MPS VII mice at 6-weeks of age (O'Connor et al, 1998).…”

Section: Discussionsupporting

confidence: 68%

“…This bodyweight change may be attributed, at least partially, to the systemic metabolic defects, such as hepatosplenomegaly, as liver pathology emerges as early as 3-months of age. Heavier liver weights and spleen weights have been reported in MPS IIIA mice with significant age by disease group interaction (Crawley et al, 2006;Hemsley and Hopwood, 2005). In addition, the reduced locomotor activity levels, observed in IDUA −/− mice as early as 2-months of age in an automated open-field test, may also play a role, although no differences of genotype by sex were shown in horizontal activity.…”

Section: Discussionmentioning

confidence: 96%

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Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome

2008

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Mucopolysaccharidosis type I (MPS I) is one of the most common lysosomal storage diseases with progressive neurological dysfunction. To characterize the chronological behavioral profiles and identify the onset of functional deficits in a MPS I mouse model (IDUA −/− ), we evaluated anxiety, locomotor behavior, startle, spatial learning and memory with mice at 2-, 4-, 6-and 8-months of age. In automated open-field test, IDUA −/− mice showed hypoactivity as early as 2-months of age and altered anxiety starting from 6-months of age during the initial exploratory phase, even through normal habituation was observed at all ages. In the marble-burying task, the anxiety-like compulsive behavior was normal in IDUA −/− mice at almost all tested ages, but significantly reduced in 8-month old male IDUA −/− mice which coincided with the rapid death of IDUA −/− males starting from 7-months of age. In the Morris water maze, IDUA −/− mice exhibited impaired proficient learning only at 4-months of age during the acquisition phase. Spatial memory deficits were observed in IDUA −/− mice during both 1-and 7-days probe trials at 4-and 8-months of age. The IDUA −/− mice performed normally in a novel object recognition task at younger ages until 8 month old when reduced visual cognitive memory retention was noted in the IDUA −/− mice. In addition, 8-month old IDUA −/− mice failed to habituate to repeated open-field exposure, suggesting deficits in nonaversive and non-associative memory. In acoustic startle assessment, significantly more non-responders were found in IDUA −/− , but normal performance was seen in those that did show a response. These results presented a temporal evaluation of phenotypic behavioral dysfunctions in IDUA −/− mice from adolescent to maturity, indicating the impairments, with different age of onset, in locomotor and anxiety-like compulsive behaviors, spatial learning and memory, visual recognition, and short-term non-associative memory retention. This study would also provide guidelines for the experimental designs of behavioral evaluation on innovative therapies for the treatment of MPS type I.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 96%

Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome

2008

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“…MPS IIIA B6.Cg-Sgsh mps3a ("MPS IIIA") and unaffected (wild-type or heterozygous; subsequently referred to as "normal") mice were obtained from a breeding colony maintained at the Women's and Children's Hospital (Crawley et al 2006). The genotypes of the mice were determined from a toe clip collected at 5-7 days of age by extracting genomic DNA by overnight incubation at 37 C in 50 mL of 50 mM Tris, pH 8.0, 2 mM NaCl, 1 mM EDTA, 0.5% (v/v) Tween20, and 0.5% (v/v) Triton X-100 supplemented with 1.2 mg/mL proteinase K. After heating at 95 C for 10 min, 1-2 mL of clarified lysate was amplified with forward primer 5 0 -NNT CTG TCT TCC TCA GCG-3 0 , reverse primer 5 0 -GAT AAG GCT GTG GCG GGA CAG GG-3 0 (final concentration of 4 ng/mL of each primer), 0.2 mM dNTP (Roche, Mannheim, Germany), and 1.25 U HotStarTaq DNA Polymerase (Qiagen, Doncaster, Australia) in a 50 mL reaction by denaturing at 94 C for 15 min followed by 35 cycles of 94 C for 45 s, 55 C for 45 s, and 72 C for 40 s, and a 5 min final extension at 72 C. After visualization of the 105 bp PCR product, amplified DNA was digested with 5 U AciI (New England Biolabs, MA, USA) at 37 C before electrophoresis through a 4.5% (w/v) agarose gel.…”

Section: Mice and Genotypingmentioning

confidence: 99%

“…Several naturally occurring animal models of MPS IIIA have been identified, including a mouse model resulting from a missense mutation that causes an amino acid change from an aspartic acid to an asparagine at position 31 of the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH; EC 3.10.1.1) (Bhaumik et al 1999;Bhattacharyya et al 2001). Congenic C57BL/6 MPS IIIA mice display reduced SGSH activity resulting in accumulation of heparan sulfate-derived disaccharides, GM2 and GM3 gangliosides and unesterified cholesterol, as well as behavioral changes such as reduced learning ability in the Morris Water Maze test, changes in open field activity, and altered anxietyrelated behaviors (Crawley et al 2006;Fraldi et al 2007;Lau et al 2008Lau et al , 2010.…”

Section: Introductionmentioning

confidence: 99%

“…Considering that neutrophil elastase and cathepsin G proteolysis mobilizes hematopoietic precursor/progenitor cells into circulation (Levesque et al 2001), reduced activity of these enzymes due to interactions with heparan sulfate could potentially result in inefficient repopulation of donor-derived cells in blood and organs following BMT. Heparan sulfate-derived GlcNS-UA is elevated 15-fold in newborn MPS IIIA mouse brain, progressively increasing to maximal levels exceeding 250-fold by 13 weeks of age (Crawley et al 2006). Therefore, transplanting mice in the neonatal period, when GlcNS-UA is less abundant, may improve donor-derived cell mobilization and the efficacy of BMT.…”

Section: Introductionmentioning

confidence: 99%

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Neonatal Bone Marrow Transplantation in MPS IIIA Mice

et al. 2012

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Patients with some neurological lysosomal storage disorders (LSD) exhibit improved clinical signs following bone marrow transplantation (BMT). The failure of mucopolysaccharidosis (MPS) type IIIA patients and adult mice with the condition to respond to this treatment may relate to factors such as impaired migration of donorderived cells into the brain, insufficient enzyme production and/or secretion by the donor-derived microglial cells, or the age at which treatment is initiated. To explore these possibilities, we treated neonatal MPS IIIA mice with whole unfractionated bone marrow and observed that nucleated blood cell reconstitution occurred to a similar degree in MPS IIIA mice receiving green fluorescent protein (GFP)-expressing normal (treatment group) or MPS IIIA-GFP marrow (control group) and normal mice receiving normal-GFP marrow (control group). Further, similar distribution patterns of GFP + normal or MPS IIIA donor-derived cells were observed throughout the MPS IIIA mouse brain. We demonstrate that N-sulfoglucosamine sulfohydrolase (SGSH), the enzyme deficient in MPS IIIA, is produced and secreted in a manner proportional to that of other lysosomal enzymes. However, despite this, overall brain SGSH activity was unchanged in MPS IIIA mice treated with normal marrow and the lysosomal storage burden in whole brain homogenates did not decrease, most likely due to donor-derived cells comprising <0.24% of total recipient brain cells in all groups. This suggests that the failure of MPS IIIA patients and mice to respond to BMT may occur as a result of insufficient donor-derived enzyme production and/or uptake by host brain cells.

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Lysosomal Disorders

Brooks¹,

Fuller²

2008

Wiley Encyclopedia of Chemical Biology

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Lysosomal storage disorders are a group of over 50 different genetic diseases that result from lysosomal dysfunction. This disruption of lysosomal function can involve either a specific lysosomal hydrolase deficiency, a defect in lysosomal protein processing, or impaired lysosomal biogenesis. To appreciate the pathogenesis of lysosomal disorders fully, it is important to understand the dynamics of endosome–lysosome organelles, their capacity for the uptake and degradation of complex macromolecules, and how lysosomal biogenesis and hydrolysis are altered by substrate storage. The focus of this article will be on recognized lysosomal disorders and what is known about the composition and the function of endosome–lysosome organelles in these diseases. The lysosomal network will be discussed with a view to correlating the main site of endosome–lysosome degradation and the site of substrate accumulation in lysosomal disorders. A major unanswered question for lysosomal storage disorders is how an enzyme deficiency and the resulting storage of undegraded macromolecules impact on cells to cause organ dysfunction and disease.

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Characterization of a C57BL/6 congenic mouse strain of mucopolysaccharidosis type IIIA

Cited by 95 publications

References 31 publications

Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome

Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome

Neonatal Bone Marrow Transplantation in MPS IIIA Mice

Lysosomal Disorders

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