Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficientmice

Lysosome-associated membrane protein-2 (LAMP-2) is a highly glycosylated pr otein and an important constituent of the lysosomal membrane(1-7). Here we show that LAMP-2 deficiency in mice increases mortality between 20 and 40 d ays of age. The surviving mice are fertile and have an almost normal life s pan. Ultrastructurally, there is extensive accumulation of autophagic vacuo les 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 abnor mal and heart contractility is severely reduced. These findings indicate th at LAMP-2 is critical for autophagy. This theory is further substantiated b y the finding that human LAMP-2 deficiency(8) causing Danon's disease is as sociated with the accumulation of autophagic material in striated myocytes.