GM1-gangliosidosis is a lysosomal storage disorder in which an essential enzyme in the lysosomes is defective and cannot break down GM1. Lysosomes serve as the cell's digestive and recycling centers, stripping proteins, fats and other molecules down to their components so they can be used to assemble new molecules. Symptoms develop in childhood, in some cases shortly after birth, and include mental retardation, seizures and other problems. The outlook for patients remains bleak.
Normally, GM1 is found in the cell membrane. But previous work from d'Azzo's laboratory has shown that in patients with GM1-gangliosidosis, this lipid accumulates in other locations within the cell, including the membrane of the endoplasmic reticulum (ER). The ER is the structure where proteins are produced. GM1 accumulation in the ER membrane depletes the ER's calcium supply, disrupting the key protein-folding process. The disruption prompts the ER to target the cell for destruction.
In the current study, investigators extended their search for answers about the neurodegeneration in GM1-gangliosidosis to the mitochondria, another intracellular compartment. Some of the mitochondria are connected to the ER via the so-called mitochondria-associated ER membranes or MAMs. MAMs function like bridges, providing a route for calcium to move out of the ER and into the mitochondria. Researchers focused on the mitochondria because one of their cellular duties is to soak up and store excess intracellular calcium, including calcium from the ER.
Using a variety of techniques, researchers identified a region within MAMs where GM1 not only accumulates but sets the stage for step two of the calcium imbalance that triggers cellular suicide. Investigators reported that in healthy cells these regions, known as glycosphingolipid-enriched microdomains, or GEMs, include tiny amounts of GM1. But in mice lacking the enzyme to break down GM1, large amounts of this li
|Contact: Summer Freeman|
St. Jude Children's Research Hospital