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Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice

Nature volume 406, pages 902–906 (2000)Cite this article

Abstract

Lysosome-associated membrane protein-2 (LAMP-2) is a highly glycosylated protein and an important constituent of the lysosomal membrane1,2,3,4,5,6,7. Here we show that LAMP-2 deficiency in mice increases mortality between 20 and 40 days of age. The surviving mice are fertile and have an almost normal life span. Ultrastructurally, there is extensive accumulation of autophagic vacuoles in many tissues including liver, pancreas, spleen, kidney and skeletal and heart muscle. In hepatocytes, the autophagic degradation of long-lived proteins is severely impaired. Cardiac myocytes are ultrastructurally abnormal and heart contractility is severely reduced. These findings indicate that LAMP-2 is critical for autophagy. This theory is further substantiated by the finding that human LAMP-2 deficiency8 causing Danon's disease is associated with the accumulation of autophagic material in striated myocytes.

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Figure 1: LAMP-2 deficiency causes increased mortality and loss of weight.
Figure 2: Accumulation of autophagic vacuoles in LAMP-2 deficient tissues.
Figure 3: Skeletal and cardiac muscles of a 19-month-old LAMP-2-deficient mouse.
Figure 4: Accumulation of autophagic vacuoles and prolonged half-time of long-lived proteins in LAMP-2-deficient hepatocyte cultures.

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Acknowledgements

We thank N. Leister, A. Wais, M. Grell, G. Jopp and D. Niemeier for technical assistance; K. Rajewski for the E-14-1 cell line; and O. Schunck and K. Nebendahl for veterinary advice. Y.T. was supported in part by the Mochida Memorial Foundation for Medical and Pharmaceutical Research and the Yamanouchi Foundation for Research on Metabolic Disorders. A.S. was supported by a fellowship of the Boehringer Ingelheim Fonds. This work was supported by the Deutsche Forschungsgemeinschaft.

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Author notes

  1. Yoshitaka Tanaka

    Present address: Pharmaceutical Cell Biology, Kyushu University, Graduate School of Pharmaceutical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan

  2. Eeva-Liisa Eskelinen

    Present address: Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland, 21205, USA

  3. Yoshitaka Tanaka, Gundula Guhde, Dieter Hartmann and Renate Lüllmann-Rauch: These authors contributed equally to this work

Authors and Affiliations

  1. Zentrum Biochemie und Molekulare Zellbiologie, Abt. Biochemie II, Universität Göttingen, Heinrich-Düker-Weg 12, Göttingen, 37073, Germany

    Yoshitaka Tanaka, Gundula Guhde, Anke Suter, Judith Blanz, Kurt von Figura & Paul Saftig

  2. Department of Biological Sciences, University of Dundee, Dundee, DD1 4NH, UK

    Eeva-Liisa Eskelinen

  3. Institute of Biotechnology, University of Helsinki, Helsinki, 0001A, Finland

    Eeva-Liisa Eskelinen

  4. Anatomisches Institut, Christian Albrechts Universität Kiel, Kiel, 24118, Germany

    Dieter Hartmann & Renate Lüllmann-Rauch

  5. Abteilung Kardiologie und Pneumologie Universität Göttingen, Robert-Koch-Strasse 40, Göttingen, D-37075, Germany

    Paul M. L. Janssen

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Correspondence to Paul Saftig.

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Tanaka, Y., Guhde, G., Suter, A. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902–906 (2000). https://doi.org/10.1038/35022595

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