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Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

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JIMD Reports - Case and Research Reports, Volume 13

Part of the book series: JIMD Reports ((JIMD,volume 13))

Abstract

Neurological dysfunction is common in humans and animals with lysosomal storage diseases. β-Mannosidosis, an autosomal recessive inherited disorder of glycoprotein catabolism caused by deficiency of the lysosomal enzyme β-mannosidase, is characterized by intracellular accumulation of small oligosaccharides in selected cell types. In ruminants, clinical manifestation is severe, and neuropathology includes extensive intracellular vacuolation and dysmyelination. In human cases of β-mannosidosis, the clinical symptoms, including intellectual disability, are variable and can be relatively mild. A β-mannosidosis knockout mouse was previously characterized and showed normal growth, appearance, and lifespan. Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no hypomyelination. This study characterized distribution of brain pathology in older mutant mice, investigating the effects of two strain backgrounds. Morphological analysis indicated a severe consistent pattern of neuronal vacuolation and disintegrative degeneration in all five 129X1/SvJ mice. However, the mice with a mixed genetic background showed substantial variability in the severity of pathology. In the severely affected animals, neuronal vacuolation was prominent in specific layers of piriform area, retrosplenial area, anterior cingulate area, selected regions of isocortex, and in hippocampus CA3. Silver degeneration reaction product was prominent in regions including specific cortical layers and cerebellar molecular layer. The very consistent pattern of neuropathology suggests metabolic differences among neuronal populations that are not yet understood and will serve as a basis for future comparison with human neuropathological analysis. The variation in severity of pathology in different mouse strains implicates genetic modifiers in the variable phenotypic expression in humans.

Competing interests: None declared

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Acknowledgments

Processing and staining of mouse brains was generously provided by NeuroScience Associates. This work was supported by NIDDK grant DK49782 from the National Institutes of Health to KHF, and by Michigan State University Foundation grant to KHF and KLL.

Author information

Authors and Affiliations

  1. Department of Neurology and Ophthalmology, Michigan State University, 965 Fee Road, A502D East Fee Hall, East Lansing, MI, 48824, USA

    Kathryn L. Lovell

  2. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA

    Mei Zhu, Meghan C. Drummond & Karen H. Friderici

  3. NeuroScience Associates, Knoxville, TN, USA

    Robert C. Switzer III

Authors
  1. Kathryn L. Lovell
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  2. Mei Zhu
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  3. Meghan C. Drummond
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  4. Robert C. Switzer III
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  5. Karen H. Friderici
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Corresponding author

Correspondence to Kathryn L. Lovell .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Clinical Pharmacology Unit, WSU Division of Health Sciences, Spokane, USA

    K. Michael Gibson

  3. Department of Biochemistry Genetics Unit, University of Oxford, Oxford, United Kingdom

    Garry Brown

  4. Department of Pediatrics IGMD, Tulane University Medical Center, New Orleans, Louisiana, USA

    Eva Morava

  5. Center for Child and Adolescent Medicine Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Ashok Vellodi

Appendices

Synopsis

In β-mannosidosis, the neuronal pathology observed in mice is consistent with the intellectual disability displayed in human cases, and the variation among different strains implicates genetic modifiers in variable phenotypic expression.

Author Who Serves as Guarantor

Kathryn L. Lovell, Ph.D.

Details of Funding

Processing and staining of mouse brains was generously provided by NeuroScience Associates. This work was supported by NIDDK grant DK49782 from the National Institutes of Health to KF, and by Michigan State University Foundation grant to KF and KL.

Compliance with Ethics Guidelines

Conflict of Interest

Kathryn Lovell, Mei Zhu, Meghan Drummond, Robert Switzer, and Karen Friderici declare that they have no conflict of interest. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

Informed Consent

Informed consent: not required. This article does not contain any studies with human subjects performed by any of the authors.

Use of Vertebrate Animals

All institutional and national guidelines for the care and use of laboratory animals were followed.

Details of the Contributions of Individual Authors

KLL::

designed the study, participated in perfusion and brain removal, analyzed results to generate distribution of pathology, took a lead role in writing the manuscript.

MZ::

produced the mutant mice, bred them for the current experiments, responsible for perfusion and brain removal, participated in writing the manuscript.

MCD::

assisted with breeding mice, assisted with analysis of data, participated in writing the manuscript.

RCS::

processed the brains for sectioning and staining, participated in photography and analysis of results, participated in writing the manuscript.

KHF::

supervised production of the mutant mice and breeding, participated in writing the manuscript.

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Lovell, K.L., Zhu, M., Drummond, M.C., Switzer, R.C., Friderici, K.H. (2013). Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Case and Research Reports, Volume 13. JIMD Reports, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_258

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  • DOI: https://doi.org/10.1007/8904_2013_258

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-54148-3

  • Online ISBN: 978-3-642-54149-0

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