Navigation Links
St. Jude Study Reveals a New Function for an Old Enzyme in Fatal Childhood Disease
Date:7/7/2008

A ubiquitous housekeeping enzyme has been found to play a major role in keeping the bone marrow environment healthy so it can nurture hematopoietic stem cells

MEMPHIS, Tenn., July 7 /PRNewswire-USNewswire/ -- 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."

In a series of experiments, d'Azzo's team discovered that the way NEU1 regulates the pool of lysosomes destined for lysosomal exocytosis is by cutting off a sugar called sialic acid from a structural protein of the lysosomal membrane, known as LAMP-1. They found that LAMP-1 is involved in the docking of lysosomes at the cell membrane, a prerequisite for these organelles to fuse with the cell membrane and release their content outside the cell. When NEU1 strips the sialic acids off LAMP-1, this protein is rapidly turned over so that its total amount is reduced. Less LAMP-1 at the lysosomal membrane influences the capacity of lysosomes to dock at the cell membrane and to engage in lysosomal exocytosis into the bone marrow environment.

"The evidence strongly suggests that in children lacking a normal gene for NEU1, disruption of the bone marrow environment causes the exodus of hematopoietic cells from the marrow to the spleen," d'Azzo said. "That leads to development of the symptoms of sialidosis. Although we don't have a cure for this terrible disease, we are now beginning to identify alternative ways to improve the disease outcome in affected children."

These findings offer new insight into why bone marrow transplants do not work in humans who lack the neu1 gene, d'Azzo said. Bone marrow cells transplanted into patients should normally home in the bone marrow niche and stay there until they mature. But if the bone marrow environment is hostile because of the loss of NEU1, the donated stem cells migrate out of the marrow and the transplant fails.

"The exciting thing about this work is that it sheds light on two major issues: the cause of sialidosis and the reason for bone marrow transplantation failure in the absence of NEU1," d'Azzo said. "This wealth of new information gives us a better understanding of the physiological function of NEU1, which appears to be much broader than originally thought. This illustrates the important role of basic research in making discoveries that have major implications for medical problems."

Other authors of this paper include Erik Bonten, Diantha van de Viekkert, Huimin Hu, Simon Moshiach and Samuel Connell (St. Jude) and Gouri Yogalingam (formerly of St. Jude).

This work was supported by the National Institutes of Health, the Assisi Foundation of Memphis and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.


'/>"/>
SOURCE St. Jude Children's Research Hospital
Copyright©2008 PR Newswire.
All rights reserved

Related medicine news :

1. 98% of Elective Mastectomy Patients Would Have Reconstruction Again, Says ASPS Study
2. 98 percent of elective mastectomy patients would have reconstruction again, says ASPS study
3. MDS Pharma Services Launches Next Generation Phase I Study Management System
4. Geisinger study: PTSD causes early death from heart disease
5. Aggressive treatment of childhood eczema could help prevent asthma, says new study
6. New study finds coronary arterial calcium scans help detect overall death risk in the elderly
7. Study: 9/11 Dogs Suffered Few Health Effects
8. Penn animal study identifies new DNA weapon against avian flu
9. Researcher receives $4 million from RWJ Foundation to study health quality reform project
10. NYU, Rutgers study shows how using mental strategies can alter the brains reward circuitry
11. Researchers study hidden homicide trend
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/10/2016)... ... 2016 , ... LaserShip, a regional parcel carrier that services the eastern U.S., ... last Friday in order to aid in the Flint water crisis. In 2014, LaserShip ... located in Clio, only 15 miles away from Flint. , “We have deep roots ...
(Date:2/10/2016)... ... February 10, 2016 , ... InDemand Interpreting ... Healthcare, recently partnered with Heart City Health Center to improve access ... years, Heart City Health Center has provided the Elkhart community with access to ...
(Date:2/10/2016)... ... , ... 10 Best Water is excited to announce a new ... that topped the list as a result of their commitment to offering clients creative, ... Tibet 5100, a top notch water company that specializes in providing the public with ...
(Date:2/10/2016)... , ... February 10, 2016 , ... ... organization, welcomes S.S. Nesbitt as the latest addition to its growing list of ... other locations throughout the Southeast, from Orlando to Huntsville and in between. , ...
(Date:2/10/2016)... ... February 10, 2016 , ... ... measure change in their patients. Research shows that the Goal Attainment Scale (GAS) ... therapists overcome this challenge and learn more about the Goal Attainment Scale, Education ...
Breaking Medicine News(10 mins):
(Date:2/11/2016)... 11, 2016 SI-BONE, Inc., a medical ... iFuse Implant System, a minimally invasive surgical (MIS) ... the sacroiliac (SI) joint, announced the publication of ... MIS SI joint fusion for patients suffering from ... or SI joint disruption.  In the first article, ...
(Date:2/11/2016)... CITY, Calif. , Feb. 11, 2016  AcelRx ... a podium presentation will be made at the 38th ... and Wound Care Symposium, which is being held ... This international conference covers the latest advancements in wound ... by the American Burn Association, Australian-New Zealand Burns Association, ...
(Date:2/11/2016)... , Feb. 11, 2016  NanoViricides, Inc. ... it has entered into an agreement with the ... nanoviricides® drug candidates in standard animal models of ... , Research Director. Dr. Romanowski has extensive experience ... --> Eric Romanowski , Research ...
Breaking Medicine Technology: