MLIV Case Study

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TRPML1’s Impact on MLIV
In the article, “Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV” discussed the impacts of TRMPL1 on MLIV. Lysosomes are important in maintaining healthy cells, however, with the absence of lysosomal TRP channel TRPML1 then the lysosomal pH becomes more acidic because of the calcium leakage; hence, this makes lysosomes more sensitive to fusing, and due to being near exocytosis regulating secretory granules in polarized secretory cells, phagocytosis occurs between the two organelles to create a larger organelle. This enlargement fusion and absence of TRPML1 cause lysosomal storage disease (LSD) Mucolipidosis type IV (MLIV). MLIV is an
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Therefore, they further explored the effects of an enhanced exocytosis and came up with the following results: enlarged granules; co-localization and co-immunoprecipitation (Co-IP) of granule and lysosomal markers in fusion; lysosomal acid phosphatase (AP) and other content secretion; and the development of pancreatitis. The researchers first observed the TRPML1-1- pancreatic acini, a non-excitable cell that has calcium-dependent exocytosis. They found that without TRPML1, there was a hyporesponsiveness of acini to low cholecystokinin (CCK) concentrations stimulation; hence, a reduce calcium secretion occurred. This response required NAADP generation and TPC2 activation that needed to be secreted from the lysosome. In contrast, at high [CCK], IP3 generations dominates response and cell stimulation between wild-type (WT) and TRPML1-1- acini showed no differences (Park et al., 2016). A regulated exocytosis in pancreatic acini processes in two phases: a less than five-minute rapid calcium-dependent phase and a PKC-stimulated phase that is stimulated by high calcium concentrations. The researchers witnessed no change at 0.3 to 10 pM CCK in acini stimulation for five minutes, but at 10-100 pM [CCK], during 30-minute stimulation, they observed an enhanced exocytosis. Therefore, they experimented with other barriers of exocytosis such as amylase content, Rab5, and changing pH of lysosome with ammonium, but they had no change in exocytosis. They also saw that the pancreatic acini secretory granules by TEM increased. They decided to

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