St. Jude Study Reveals a New Function for an Old Enzyme in Fatal Childhood Disease
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
www.stjude.org.
Source: St. Jude Children's Research Hospital
CONTACT: Carrie Strehlau, +1-901-595-2295, carrie.strehlau@stjude.org,
or Summer Freeman, +1-901-595-3061, summer.freeman@stjude.org,
both of St.
Jude Public Relations
Web Site: http://www.stjude.org/
 |
