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Brain, Vol. 125, No. 3, 551-561, May 2002
© 2002 Guarantors of Brain

Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation

James Y. Garbern1, Donald A. Yool7, Gregory J. Moore2, Ian B. Wilds2, Michael W. Faulk2, Matthias Klugmann6, Klaus-Amin Nave6, Erik A. Sistermans4, Marjo S. van der Knaap5, Thomas D. Bird3, Michael E. Shy1, John A. Kamholz1 and Ian R. Griffiths7

1 Department of Neurology and Center for Molecular Medicine and Genetics, 2 Department of Psychiatry and Behavioral Sciences, Wayne State University School of Medicine, Detroit, Michigan, 3 Department of Neurology, University of Washington and Seattle Veterans Administration Medical Center, Seattle, Washington, USA, 4 Department of Human Genetics, University Medical Centre Nijmegen, 5 Free University Medical Center, Amsterdam, The Netherlands, 6 Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, Germany and 7 Applied Neurobiology Group, Department of Veterinary Clinical Studies, University of Glasgow, Bearsden, Glasgow, UK

Correspondence to: James Garbern, Department of Neurology and Center for Molecular Medicine and Genetics, 421E. Canfield Room 3206, Wayne State University School of Medicine, Detroit, MI 48201, USA E-mail: jgarbern{at}med.wayne.edu

Axonal degeneration contributes to clinical disability in the acquired demyelinating disease multiple sclerosis. Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent. To explore the importance of interactions between oligodendrocytes and axons in the CNS, we analysed the brains of rodents and humans with a null mutation in the gene encoding the major CNS myelin protein, proteolipid protein (PLP1, previously PLP). Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate axonal and myelin integrity. In vivo proton magnetic resonance spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N-acetyl aspartate (NAA), a marker of axonal integrity. Length-dependent axonal degeneration without demyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1-deficient patients showed reduced NAA levels, consistent with axonal loss. Analysis of patients’ brain tissue also demonstrated a length-dependent pattern of axonal loss without significant demyelination. Therefore, axonal degeneration occurs in humans as well as mice lacking the major myelin protein PLP1. This degeneration is length-dependent, similar to that found in the PNS of patients with the inherited demyelinating neuropathy, CMT1A, but is not associated with significant demyelination. Disruption of PLP1-mediated axonal–glial interactions thus probably causes this axonal degeneration. A similar mechanism may be responsible for axonal degeneration and clinical disability that occur in patients with multiple sclerosis.


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