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Role Found for Protein in Kidney Disease

Marriage of Brain Receptors Breeds Synapses

Few Links Shown Between Iron Level, Heart Disease Risk

Transplanted Fetal Nerve Cells Thrive in Brain



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RESEARCH BRIEFS

Role Found for Protein in Kidney Disease

A new study by re-searchers at HMS and Massachusetts General Hospital is the first to establish the function of one of two proteins implicated in autosomal dominant polycystic kidney disease, an inherited disorder in which the formation of renal cysts leads to progressive destruction of normal tissue and end-stage kidney failure in one out of every 400 to 1,000 people. The most common human disease linked to a single gene, it is caused by mutations in either of the genes that code for two transmembrane proteins, polycystin-1 and polycystin-2. Previous studies have shown that the two interact in the cytoplasm, and it has been suggested, though not demonstrated, that polycystin-1 binds polycystin-2 and regulates its activity as an ion channel.

Immunostaining of human syncytiotrophoblast, a membrane in the placenta, shows the distribution of polycystin-2. Researchers at HMS and Massachusetts General Hospital have discovered that this protein functions as an ion channel, helping elucidate its role in kidney disease. Courtesy of M. Amin Arnaout


Now, researchers led by Keetae Kim, HMS research fellow in medicine at MGH, and Silvia González-Perrett of the Facultad de Farmacia y Bioquímica in Buenos Aires, report results of studies on human placental tissue showing that polycystin-2 does, in fact, function as an ion channel. In the placenta, it helps to regulate the transport of electrolytes between mother and fetus. Thus, mutations in polycystin-2, found in 10 to 15 percent of patients with autosomal dominant polycystic kidney disease, may directly impair normal ion transport in affected tissues and lead to cyst formation. Furthermore, defects in polycystin-1, present in 85 percent of cases of the disease, also may disrupt the normal channel activity of polycystin-2 via interaction between the two proteins.

Autosomal dominant polycystic kidney disease "is associated with fluid-filled cysts where altered electrolyte transport, including Na+, Cl-, and possibly Ca2+, has been implicated in the onset of the disease," the authors write. "The channel properties of polycystin-2 may now help explain some of these functional features." Co-authors of the study, which is published in the Dec. 26 PNAS Early Edition, include M. Amin Arnaout, professor of medicine, and Horacio Cantiello, associate professor of medicine, both at MGH, and scientists at the Facultad de Medicina in Buenos Aires and the Mayo Clinic in Rochester, Minn.

Marriage of Brain Receptors Breeds Synapses

In trying to answer the old question of how synapses form in the developing brain, scientists have broadened the purview of an already powerful family of brain proteins. In the Dec. 8 Cell, HMS research fellow in neurology Matthew Dalva, graduate student Mari Takasu, and others report that when EphB receptors lodged in the membranes of neurons are stimulated by their ligand proteins, they form clusters with NMDA receptors. These ion channels respond to the neurotransmitter glutamate in excitatory synapses. Moreover, the scientists found that tinkering with this receptor clustering affected how many synapses formed on neurons cultured in vitro.

Led by Michael Greenberg, HMS professor of neurology at Children's Hospital, this study is significant for two reasons. First, it interweaves the previously separate functions attributed to these two classes of receptors. EphB receptors are thought to act mainly as "Do not enter" signs that keep growing axons heading in the right direction. NMDA receptors are involved in synaptic plasticity, learning, and the triggering of cell death by overexcitation.

Second, it gives researchers a handle on understanding synapse formation in the brain. In the past decade, scientists have uncovered a series of molecular steps required to build a peripheral synapse (between nerve and muscle) but have had no such luck with its more complex, central counterpart until now. Interestingly, the results presented in the current paper parallel findings on the peripheral synapses in that receptors from the same broad category, the receptor tyrosine kinases, induce the clustering of previously dispersed neurotransmitter receptors into tightly focused spots that then go on to form a mature synapse.

Few Links Shown Between Iron Level, Heart Disease Risk

For centuries, blood-letting was a staple of medical practice, used by physicians to treat ailments ranging from fever to syphilis to insanity. Although bleeding patients has been out of fashion in recent years, some researchers have wondered whether a little blood loss, such as that experienced by menstruating women, might be good for reducing coronary heart disease risk. A new study from the Harvard School of Public Health suggests that leeches and scalpels may not find a new niche in preventive medicine after all.

The hypothesis was based on the observation that iron overload in experimental animals promotes atherosclerosis and ischemic myocardial damage. If high iron levels in the blood increase heart disease risk, this might also help account for the lower heart disease risk of premenopausal women compared to men and older women. A mechanism was proposed in which iron might promote disease by catalyzing the formation of reactive oxygen species and promoting lipid peroxidation.

Epidemiologists have tried to test this theory in various ways, but all have had problems such as imprecise measurement or potential confounding factors. In the new study, published in the Jan. 2 Circulation, a group of HSPH and HMS researchers led by Alberto Ascherio, associate professor of nutrition and epidemiology at HSPH, used an indirect way to measure iron levels—blood donation history. Men donating one unit of blood a year halve their level of iron stores, and giving two or three units brings the level down to that of premenopausal women. As part of the Health Professionals Follow-up Study, Ascherio and colleagues collected information on blood donation from 38,244 men not known to have cardiovascular disease in 1992 and looked at subsequent myocardial infarction rates in donors and nondonors. The biggest difference they found was that men who had given the most blood (30 or more units) had a 20 percent greater risk of heart attack over the follow-up period. The trend was not statistically significant, however.

"Differences in coronary risk factors between blood donors and never donors were modest," they report. "The results of our study suggest that body iron stores are not a major coronary risk factor among U.S. men without previous cardiovascular disease or diabetes."

Transplanted Fetal Nerve Cells Thrive in Brain

Human fetal neurons transplanted into the brain of a 54-year-old man with Huntington's disease survived 18 months and appeared un-touched by the cellular destruction raging around them, McLean Hospital and HMS researchers report in the Dec. 5 PNAS.

"This is the first demonstration that these cells can survive—and they are not affected by the genetic disease of the surrounding cells," said Francesca Cicchetti, HMS research fellow at McLean's Neuroregeneration Labs. She and Thomas Freeman of the University of South Florida are lead authors on the paper.

The team introduced 10 whole fetal striata into the brains of each of seven Huntington's patients. When one died suddenly of a heart attack, they found that most of the fetal implants had taken root in the man's striatum, and they lacked the poisonous protein clumps found in the surrounding sick cells. It is not known whether the transplanted cells functioned in the patient's brain or produced clinical improvement. But another recent study using functional MRI found significant functional changes in the brains of Huntington's patients who received fetal cells. The fact that they were able to thrive a year and a half after transplantation is good news for those seeking to use stem cells to replace the damaged or missing neurons in Huntington's and other neurodegenerative diseases.

"Stem cells need to be coaxed into becoming fetal neurons," said co-author Ole Isacson, HMS associate professor of neurology (neuroscience) and director of McLean's Neuroregeneration Labs. "If fetal cells work in Parkinson's and Huntington's disease, then all the claims made for stem cells will be more realistic." In earlier studies, Isacson and his colleagues found that transplanting fetal cells restored function to animals with Huntington's-like damage and symptoms. "The question is what kinds of development we need in order to have success in patients," he said.