1. Zentrum Biochemie und Molekulare Zellbiologie, Abt. Biochemie II, Universität Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany
2. University of Dundee, Department of Biological Sciences, Dundee DD1 4NH, UK
3. Institute of Biotechnology, University of Helsinki, 0001A Helsinki, Finland
4. Anatomisches Institut, Christian Albrechts Universität Kiel, 24118 Kiel, Germany
5. Abteilung Kardiologie und Pneumologie, Universität Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany
6. These authors contributed equally to this work
7. Present addresses: Kyushu University, Graduate School of Pharmaceutical Sciences, Pharmaceutical Cell Biology, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan (Y.T.) and Johns Hopkins University, Institute of Molecular Cardiobiology, Baltimore, Maryland 21205, USA (E.-L.E.).

Correspondence to: Paul Saftig¹ Correspondence and requests for materials should be addressed to P.S. (e-mail: Email: saftig@uni-bc2.gwdg.de).

Abstract

Lysosome-associated membrane protein-2 (LAMP-2) is a highly glycosylated protein and an important constituent of the lysosomal membrane^{1, 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.