Fusion of Lysosomes with Secretory Vesicle Leads to Excessive Uncontrolled Exocytosis in Mucolipidosis Type IV

Mutations in TRPML1 cause the lysosomal storage disease (LSD) Mucolipidosis type IV (MLIV), which is characterized by neurodegeneration, muscular hypotonia corneal opacity, achlorhydia, anemia and severe psychomotor deficiency with impaired neuromuscular junctions. The role of the TRP channel TRPML1 in cell function and how mutations in TRPML1 cause MLIV are not well understood. Studies on the causes of MLIV are focused on the potential role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, the role of TRPML1 in secretory cells that their cardinal function is regulated exocytosis has not been studied. Here, we analyzed several forms of regulated exocytosis in neurons and secretory epithelia in a knockout mouse model of TRPML1 and, unexpectedly, found excessive exocytosis due to marked enlargement of synaptic vesicles and secretory granules due to fusion with lysosomes. As a result, Trpml1−/− neurons maintain high basal and stimulated exocytosis of the neurotransmitter and neurotoxin glutamate, which may account for the neurodegeneration in ML4. Trpml1−/− pancreatic and salivary glands acini show high Ca2+− and cAMP-stimulated exocytosis, resulting in pancreatitis. These features were not found in another model of LSD, the Niemann-Pick disease type C1 mouse model. These findings indicate that a major role of TRPML1 is to guard against pathological fusion of lysosomes with other intracellular organelles, including secretory vesicles, and suggest a new approach towards developing treatment for MLIV.