LAMP2

Abstract: "Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.

Abstract: Chaperone-mediated autophagy (CMA) is a selective type of autophagy by which specific cytosolic proteins are sent to lysosomes for degradation. Substrate proteins bind to the lysosomal membrane through the lysosome-associated membrane protein type 2A (LAMP-2A), one of the three splice variants of the lamp2 gene, and this binding is limiting for their degradation via CMA. However, the mechanisms of substrate binding and uptake remain unknown. We report here that LAMP-2A organizes at the lysosomal membrane into protein complexes of different sizes. The assembly and disassembly of these complexes are a very dynamic process directly related to CMA activity. Substrate proteins only bind to monomeric LAMP-2A, while the efficient translocation of substrates requires the formation of a particular high-molecular-weight LAMP-2A complex. The two major chaperones related to CMA, hsc70 and hsp90, play critical roles in the functional dynamics of the LAMP-2A complexes at the lysosomal membrane. Thus, we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes, whereas the presence of lysosome-associated hsp90 is essential to preserve the stability of LAMP-2A at the lysosomal membrane.