Late motor decline after accomplished remyelination: Impact for progressive multiple sclerosis
Natalia Manrique-Hoyos MSc
Max Planck Institute for Experimental Medicine; Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Search for more papers by this authorTanja Jürgens MSc
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany
Search for more papers by this authorMads Grønborg PhD
Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Germany
Search for more papers by this authorMario Kreutzfeldt MSc
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany
Search for more papers by this authorMariann Schedensack
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Search for more papers by this authorTanja Kuhlmann MD
Institute of Neuropathology, University Hospital Münster, Münster, Germany
Search for more papers by this authorChristina Schrick
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Search for more papers by this authorWolfgang Brück MD
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Search for more papers by this authorHenning Urlaub PhD
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Germany
Search for more papers by this authorCorresponding Author
Mikael Simons MD
Max Planck Institute for Experimental Medicine; Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Department of Neurology, University Medical Center, Georg August University, Göttingen, Germany
M.S. and D.M. contributed equally to this work.
Max-Planck-Institute of Experimental Medicine, Hermann-Rein Str. 3, 37075, Göttingen, GermanySearch for more papers by this authorDoron Merkler MD
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany
Search for more papers by this authorNatalia Manrique-Hoyos MSc
Max Planck Institute for Experimental Medicine; Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Search for more papers by this authorTanja Jürgens MSc
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany
Search for more papers by this authorMads Grønborg PhD
Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Germany
Search for more papers by this authorMario Kreutzfeldt MSc
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany
Search for more papers by this authorMariann Schedensack
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Search for more papers by this authorTanja Kuhlmann MD
Institute of Neuropathology, University Hospital Münster, Münster, Germany
Search for more papers by this authorChristina Schrick
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Search for more papers by this authorWolfgang Brück MD
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Search for more papers by this authorHenning Urlaub PhD
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Germany
Search for more papers by this authorCorresponding Author
Mikael Simons MD
Max Planck Institute for Experimental Medicine; Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Department of Neurology, University Medical Center, Georg August University, Göttingen, Germany
M.S. and D.M. contributed equally to this work.
Max-Planck-Institute of Experimental Medicine, Hermann-Rein Str. 3, 37075, Göttingen, GermanySearch for more papers by this authorDoron Merkler MD
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany
Search for more papers by this authorAbstract
Objective:
To investigate the impact of single or repeated episodes of reversible demyelination on long-term locomotor performance and neuroaxonal integrity, and to analyze the myelin proteome after remyelination and during aging.
Methods:
Long-term locomotor performance of previously cuprizone-treated animals was monitored using the motor skill sequence (MOSS). Quantitative analysis of myelin proteome and histopathological analysis of neuronal/axonal integrity was performed after successful remyelination. Histopathological findings observed in experimental chronic remyelinated lesions were verified in chronic remyelinated lesions from multiple sclerosis (MS) patients.
Results:
Following cessation of cuprizone treatment, animals showed an initial recovery of locomotor performance. However, long after remyelination was completed (approximately 6 months after the last demyelinating episode), locomotor performance again declined in remyelinated animals as compared to age-matched controls. This functional decline was accompanied by brain atrophy and callosal axonal loss. Furthermore, the number of acutely damaged amyloid precursor protein–positive (APP+) axons was still significantly elevated in long-term remyelinated animals as compared to age-matched controls. Confocal analysis revealed that a substantial proportion of these APP+ spheroids were ensheathed by myelin, a finding that was confirmed in the chronic remyelinated lesions of MS patients. Moreover, quantitative analysis of myelin proteome revealed that remyelinated myelin displays alterations in composition that are in some aspects similar to the myelin of older animals.
Interpretation:
We propose that even after completed remyelination, axonal degeneration continues to progress at a low level, accumulating over time, and that once a threshold is passed axonal degeneration can become functionally apparent in the long-term. The presented model thus mimics some of the aspects of axonal degeneration in chronic progressive MS. ANN NEUROL 2012;71:227–244
Supporting Information
Additional Supporting Information can be found in the online version of this article.
| Filename | Description |
|---|---|
| ANA_22681_sm_SuppTab1.pdf73.3 KB | Supporting Table 1. Summary of proteins identified in myelin samples from mice labeled with iTRAQ and analysed with LC-MS/MS. |
| ANA_22681_sm_SuppTab2to4.pdf273 KB | Supporting Table 2, 3 and 4. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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