| GM1-ganglioside beta-galactosidase (GM1ase, 3.2.1.23) is a well-characterized acidic beta-galactosidase that resides in the lysosome of specific mammalian cells. We show high levels of acidic beta-galactosidase activity in the salivary glands of mice, rabbits and humans (Nowroozi et al., 1998; 1999a; 1999b). GM1-ganglioside, the physiological substrate of GM1ase in neural tissues, is a sialic acid containing glycolipid that resides in the mammalian plasma membrane and is catabolized by GM1ase after its internalization into the lysosome. The deficiency of GM1ase in man, GM1-gangliosidosis, is characterized by deep mental retardation, reflecting the lysosomal storage of GM1-ganglioside. We show unexpectedly high levels of GM1-ganglioside in the mammalian parotid glands, and characterize knockout mouse models for GM1-gangliosidosis (Hahn et al., 1997; Matsuda et al., 1997). Histopathologically, a generalized degenerative storage disease in the form of large (>10 mum in diameter) vacuolar structures is visible in the parotid gland. We demonstrate that storage materials in these vacuolar structures contain high levels of GM1-ganglioside and over 5-fold increased level of GM1-ganglioside in the GM1ase knockout mice parotid glands. Electron microscopic data demonstrates additional vacuolar structures (1--2 mum in diameter) located in the cis-side of Golgi apparatus. Fragmentation and vesiculation of rough endoplasmic reticulum is also noted. We further observe impairment of the secretory function of the parotid glands of GM1ase deficient mice following beta-adrenergic stimulation---over 6-fold reduced alpha-amylase secretion. These results suggest that the parotid gland utilizes secretory cellular mechanisms involving GM1-ganglioside that are similar to those employed by some neural cells and are different from those present in submandibular and sublingual glands. These mechanisms may be related to the newly characterized caveolae, or caveolae-like (raft) membrane structures which are rich in GM1-ganglioside. |
