Abstract:

Lysosome-associated membrane protein-2 (LAMP-2) is the gene responsible for Danon disease, which is characterized by cardiomyopathy, autophagic vacuolar myopathy, and variable mental retardation. To elucidate the function of LAMP-2 in the central nervous system, we investigated the neuropathological changes in Lamp-2-deficient mice. Immunohistochemical observations revealed that Lamp-1 and cathepsin D-positive lysosomal structures increased in the large neurons of the mouse brain. Ubiquitin-immunoreactive aggregates and concanavalin A-positive materials were detected in these neurons. By means of ultrastructural studies, we found various-shaped accumulations, including lipofuscin, glycolipid-like materials, and membranous structures, in the neurons and glial cells of Lamp-2-deficient brains. In deficient mice, glycogen granules accumulated in hepatocyte lysosomes but were not observed in neurons. These pathological features indicate lysosomal storage disease; however, the findings are unlikely a consequence of deficiency of a single lysosomal enzyme. Although previous study results have shown a large amount of autophagic vacuoles in parenchymal cells of the visceral organs, these findings were rarely detected in the brain tissue except for some axons in the substantia nigra, in which abundant activated microglial cells with increased lipid peroxidation were observed. Thus, LAMP-2 in the central nervous system has a possible role in the degradation of the various macromolecules in lysosomes and an additional function concerning protection from oxidative stress, especially in the substantia nigra.

日本語要旨:

Lamp-2遺伝子変異はDanon病、自己貪食空胞性ミオパチー、精神遅滞などを引き起こす。中枢神経系におけるLamp-2の機能を解明するため、Lamp-2欠損マウスを神経病理学的に解析した。Lamp-2欠損マウスの脳ではLamp-1、カテプシンがライソゾームに沈着しており、リポフスチン、糖脂質様物質の凝集が観察された。この結果から中枢神経系においてLamp-2は、ライソゾームによる様々な高分子の分解に関与し、酸化ストレスに対する防御にも関わると考えられる。