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Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet

Nature Medicine volume 18, pages 1130–1135 (2012)Cite this article

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Abstract

Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher disease (PMD), a fatal leukodystrophy1 without therapeutic options2,3. PLP binds cholesterol and is contained within membrane lipid raft microdomains4. Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis5. Transgenic mice with extra copies of the Plp1 gene6 are accurate models of PMD. Dysmyelination6,7,8 followed by demyelination9,10, secondary inflammation and axon damage contribute to the severe motor impairment in these mice9,10. The finding that in Plp1-transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes)9,11,12,13, prompted us to further investigate the role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellular PLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD.

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Figure 1: Cholesterol prevents the clinical deterioration of PMD mice.
Figure 2: Short-term cholesterol treatment delays PMD pathology.
Figure 3: Long-term cholesterol diet preserves myelin in PMD mice.
Figure 4: Abnormal subcellular cholesterol distribution in PMD oligodendrocytes

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Acknowledgements

We dedicate this work to the memory of Jim Garbern for his support of PMD research. We are grateful to A. Fahrenholz, T. Freerck, M. Schildmann, M. Matthes and A. Kanbach for technical support and thank J. Edgar for helpful comments on the manuscript. We thank M. Grebe (Umea University) for providing the BCθ expression construct and Pfizer for the generous gift of the squalestatin CP-340868. This work was funded by the PMD foundation and the Deutsche Forschungsgemeinschaft (SA2114/1-1) to G.S. K.-A.N. is supported by the EU-FP7 (Leukotreat, Ngidd), the Bundesministerium für Bildung und Forschung (BMBF; Leukonet) and a European Research Council (ERC) Advanced Grant. Support of the BMBF to S.L. and K.-F.S. is gratefully acknowledged (01GQ0810).

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Author notes

  1. Fabian Rudolphi and Kristina Corthals: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    Gesine Saher, Fabian Rudolphi, Kristina Corthals, Torben Ruhwedel, Payam Dibaj, Benoit Barrette, Wiebke Möbius & Klaus-Armin Nave

  2. Bernstein Focus Neurotechnology and Johann-Friedrich-Blumenbach Institute of Zoology and Anthropology, Georg-August University, Göttingen, Germany

    Karl-Friedrich Schmidt & Siegrid Löwel

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  1. Gesine Saher
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Contributions

G.S. supervised the project, conducted experiments and wrote the manuscript; F.R., K.C. and T.R. conducted experiments, K.-F.S. and S.L. performed visual acuity measurements, P.D. conducted the two-photon microscopic analysis, B.B. implemented the beam test, W.M. supervised and contributed to electron microscopic studies, and K.-A.N. contributed to the discussion and the writing of the manuscript.

Corresponding authors

Correspondence to Gesine Saher or Klaus-Armin Nave.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Table 1 (PDF 1330 kb)

Supplementary Video 1

Motor performance of treated and untreated PMD mice. This video shows an example of a beam test that was used to evaluate motor abilities of PMD mice. (MPG 3093 kb)

Supplementary Video 2

Motor disabilities of cSQS KO and cSQS KO*PLP+/66 mice. (WMV 3826 kb)

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Saher, G., Rudolphi, F., Corthals, K. et al. Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet. Nat Med 18, 1130–1135 (2012). https://doi.org/10.1038/nm.2833

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