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Neuronal loss in Pelizaeus–Merzbacher disease differs in various mutations of the proteolipid protein 1

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Abstract

Mutations affecting proteolipid protein 1 (PLP1), the major protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus–Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.

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Acknowledgments

The authors are especially grateful to the families who generously donated specimens for research. J.G. thanks the PMD Foundation, the National Institutes of Health (NS043783), the Children’s Research Center of Michigan, and the National Multiple Sclerosis Society (RG3204) for support. G.M.H. acknowledges the Nemours Foundation and National Institutes of Health grant P20 RR-020173-01 from the National Center for Research Resources. The authors also are grateful to the Alzheimer disease Research Center of the University of Washington for assistance.

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Author notes

  1. Christopher R. Pierson

    Present address: Department of Pathology, Ohio State University, Columbus, OH, USA

Authors and Affiliations

  1. Department of Pathology, School of Medicine, Wayne State University, Detroit, MI, USA

    Anders A. F. Sima, Christopher R. Pierson & William J. Kupsky

  2. Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA

    Anders A. F. Sima, William J. Kupsky & James Y. Garbern

  3. Department of Neurosurgery, School of Medicine, Wayne State University, Detroit, MI, USA

    Anders A. F. Sima & William J. Kupsky

  4. Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA

    James Y. Garbern

  5. Department of Pathology, Oregon Health Sciences University, Portland, OR, USA

    Randall L. Woltjer

  6. Nemours Biomedical Research, A. I. duPont Hospital for Children, Wilmington, DE, USA

    Grace M. Hobson

  7. Department of Pathology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Jeffrey A. Golden

  8. Department of Genetics, Kaiser Permanente Medical Center, Oakland, CA, USA

    Galen M. Schauer

  9. Department of Pathology, Kaiser Permanente Medical Center, Oakland, CA, USA

    Galen M. Schauer

  10. Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

    Thomas D. Bird

  11. Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI, USA

    Robert P. Skoff

Authors
  1. Anders A. F. Sima
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Correspondence to James Y. Garbern.

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Sima, A.A.F., Pierson, C.R., Woltjer, R.L. et al. Neuronal loss in Pelizaeus–Merzbacher disease differs in various mutations of the proteolipid protein 1. Acta Neuropathol 118, 531–539 (2009). https://doi.org/10.1007/s00401-009-0562-8

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  • DOI: https://doi.org/10.1007/s00401-009-0562-8

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