In a rare disease called mucolipidosis type II, people’s hearts and abdomens swell, and their bones grow malformed.
A lysosomal storage disorder, mucolipidosis type II causes edema of the internal organs and skeletal dysplasia. Children diagnosed with the genetic disease often die before they reach age 7. Now, University of Michigan researchers have identified a new gene implicated in the disease, TMEM251, which is necessary for lysosomes to function correctly.
Lysosomes are organelles within all cells of the body — except red blood cells — responsible for taking in and recycling the garbage your cells produce. When the lysosome can’t function properly, it fails to recycle this garbage and instead simply stockpiles them in the organelle.
The team, led by Ming Li, assistant professor of molecular, cellular and developmental biology, discovered that if TMEM251 is defective, it fails to encode the pathway for the enzymes necessary for the correct function of lysosomes to travel inside the lysosome. The study is published in Nature Communications.
There are about 50 to 60 enzymes inside the lysosomes that digest worn-out cellular parts as well as waste from outside the cell. The lysosome also recycles this waste — proteins, nucleic acid, carbohydrates and lipids — back into usable material. But for these enzymes to travel inside the lysosome, they need a signal called the mannose-6-phosphate biosynthetic pathway, or M6P.
“It’s like a postage stamp. The enzymes have to have this signal in order to go inside the lysosome. If they don’t have M6P, they aren’t able to go into the lysosome,” Li said. “So consequently, you still have lysosomes, but not a single one of them would be functional because they lack these enzymes.”
Li’s lab studies the lysosome, and in particular, the composition of lysosome membrane proteins. The lysosome has the ability to regulate its own membrane protein by triggering the degradation of these proteins through a process called ubiquitination. This process allows proteins to travel from the membrane of the lysosome inside the organelle for degradation. The researchers also wanted to understand which genes were responsible for lysosome function and what happens when those genes are defective.
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