The therapeutic strategies for lysosomal diseases such as mucolipidosis type IV (MLIV), Tay-Sachs and Niemann-Pick are very limited. Similar to the lysosomal storage diseases, MLIV is characterized by severe neurologic and ophthalmologic abnormalities and usually presents during the first year of life with cognitive impairment and blindness. It is caused by mutations in MCOLN1, the gene encoding mucolipin-1 (MLN1), which we have recently established to be a Ca2+-permeable cation channel that is transiently modulated by Ca 2+. It is also permeable to Na +, K+, and other cations. In addition, our work has shown that naturally occurring mutant MLN1 channels are only weakly activated by increases in intracellular Ca 2+ (Cai) and show other functional abnormalities. We have characterized fibroblasts from MLIV patients and found diminished Ca2+ signaling and large lysosomes with altered cellular localization. A significant phenotypic alteration in these cells is the inhibition of lysosomal exocytosis, the terminal step in the pathway, which is a Ca 2+- independent process that plays a role in membrane resealing related to wound healing and delivery of cargo to the extracellular space. Lysosomal exocytosis is also likely to function in the removal of cellular debris near sites of cellular damage and in removal of certain waste products from the cell. It is possible that a disturbance in these processes could be implicated in corneal opacification and achlorhydria, and altered psychomotor response, all hallmarks of this tragic childhood disease. The overall goal of this study is to assess the beneficial effects of dietary compounds and related natural products in promoting lysosomal clearance in cells of MLIV and other lysosomal disorders.
The specific aims are as follows: 1) test the hypothesis that activators of lysosomal catabolic enzymes and other natural dietary products can be used to increase lysosomal clearance from cells of patients with mucolipidosis IV; 2) to determine the dose-response curves of the most effective compounds and the time-course of their actions in cells from patients with different mutations of MLN1; and 3) test the hypothesis that some agents elicit synergistic effects and exert beneficial actions on cells derived from patients with other lysosomal storage disorders such as Tay-Sachs and Niemann-Pick. In the long term, the most effective drug combination may be employed as a complementary/alternative medicine for reducing the damage of the lysosomal processes in these devastating diseases affecting mainly children of neonatal and adolescent ages.
| LaPlante, Janice M; Falardeau, John L; Brown, Edward M et al. (2011) The cation channel mucolipin-1 is a bifunctional protein that facilitates membrane remodeling via its serine lipase domain. Exp Cell Res 317:691-705 |
