The lack of a single protein usually thought of as a run-of-the-mill enzyme that helps to recycle molecules in cells causes an incurable and often fatal disease of children, according to St. Jude Children's Research Hospital investigators.
Children with this disease, called sialidosis, suffer from enlarged spleens and often develop vision problems, loss of coordination and seizures, among other symptoms. The patients generally die within the first few years of life.
St. Jude investigators showed in test tube experiments and mouse models of sialidosis that the loss of the protein NEU1 triggers a catastrophic falling of biochemical dominos that ultimately leads to disruption of normal formation of mature blood cells. A report on this work appears in the July 8, 2008, issue of the journal Developmental Cell.
"The discovery is important because it explains why patients with sialidosis have enlarged spleens and suggests that new drugs or gene therapies that target that problem might be an effective therapy," said Alessandra d'Azzo, Ph.D., a member in the St. Jude Department of Genetics and Tumor Cell Biology and the paper's senior author. "The results also explain how the loss of NEU1 can cause bone marrow transplantations to fail, and therefore suggests that such failures might also be corrected by target therapeutics."
The researchers showed that NEU1 controls how bags of digestive enzymes inside white blood cells, neutrophils and macrophages, discharge their contents into the bone marrow environment in a highly regulated process known as lysosomal exocytosis. These bags of enzymes, called lysosomes, rarely discharge their content outside of the cell. Instead, they use their enzymes inside the cell to digest no longer needed products into small building blocks that the cell can reuse or dispose.
The St. Jude team found that in the absence of NEU1, white cell lysosomes are more prone than normal lysosomes to dock and eventually fuse with the cell membrane and subsequently spill their active enzymes into the bone marrow environment. This aberrant behavior hampers the ability of hematopoietic stem cells (HSCs) to be correctly retained within the bone niche. HSCs are immature cells that give rise to all the types of blood cells in the body. The researchers showed that the released enzymes prematurely digest a protein on bone marrow stromal cells called VCAM-1, a molecule that these cells use to hold onto HSCs in the bone marrow.
Deprived of their normal nurturing environment, the HSCs migrate out of the bone marrow and into the spleen, crowding into the organ until it becomes severely enlarged. "Our work represents an unexpected and important clue to one of the prominent clinical manifestations of sialidosis patients," d'Azzo said. "We were surprised to discover that an old, ubiquitous enzyme in lysosomes better known for digesting cellular waste products plays such an important role in a basic biological process that when exacerbated contributes to the outcome of such a terrible disease in children."