U-M Biologists Find Potential Drug That Speeds Cellular Recycling

Inside the many cells that make up the human body, the job of getting rid of worn-out cellular components and wastes falls to the lysosomes. These lysosomes use a variety of digestive enzymes to take apart proteins, lipids, parts of cell membranes, and many other things. Once these materials are disassembled, they are shipped out of the lysosome to be reassembled elsewhere into new cellular compartments. The flow of the materials out of the lysosome is called vesicular trafficking and is essential for the health of the entire organism. Problems with the trafficking can cause a variety of diseases including a group of inherited metabolic disorders called lipid storage diseases. Researchers have found that proper functioning of the lysosome depends on calcium channels. If calcium channels are defective, trafficking through the lysosome stops and waste can accumulate to unhealthy levels. Researchers at the University of Michigan identified a protein called TRPML1 that serves as the calcium channel in lysosomes and a lipid known as PI(3,5)P2 opens and closes the gates of the channel. Hoaxing Xu, who led the team, and his colleagues also identified a synthetic molecule, ML-SA1, that mimics the lipid PI(3,5)P2 and can activate the calcium channels. When ML-SA1 was introduced into mouse cells and Niemann-Pick (a lipid storage disease) Type C cells, the increased flow through the lysosome's calcium channels was enough to increase trafficking and decrease lipid storage. "The idea is that for lysosome storage diseases, neurodegenerative diseases and aging, they're all caused or worsened by very reduced or slow trafficking in the cellular recycling center," said Xu. The researchers hope to administer ML-SA1 to Niemann-Pick and mucolipidosis Type IV mice to determine if the molecule alleviates symptoms. The studies are in the early, basic-research stage and any drug that might result is years away.
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