The neuronal expression and regulated proteolysis of the normal, cellular prion protein (PrPc) are essential for the maintenance of peripheral myelin, according to an international team of researchers from institutions including Cal Tech and the University Hospital of Zurich. The integrity of peripheral nerves depends on communication between axons and the Schwann cells that produce myelin. Myelin insulates peripheral nerve axons and speeds electrical transmission. The axon signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown, the authors wrote. The normal function of PrPc–that when misfolded into the scarpie-associated form (PrPsc) causes various transmissible fatal neurodegenerative diseases, including scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in humans–is also unknown. The current results appear to represent progress toward solving, at least in part, both of these puzzles. The authors showed that ablation of PrPc triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. CDP was triggered by depletion of PrPc specifically in neurons, but not in Schwann cells, and was suppressed by PrPc expression restricted to neurons but not to Schwann cells. CDP was prevented by PrPc variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrPc lacking its glycolipid membrane anchor. This work was published in the March issue of Nature Neuroscience. The seminal research identifying and characterizing prion proteins was recognized by the awarding of the Nobel Prize in Physiology or Medicine to Dr. Stanley Prusiner in 1997.
In a second study, researchers at Johns Hopkins and collaborating institutions have identified a mechanism whereby alterations in the DISC-1 (disrupted in schizophrenia-1) gene may underlie the adolescent onset of schizophrenia. In this second study, published in the March issue of Nature Neuroscience, the research team examined DISC-1’s role in forming connections between nerve cells. The first study looked at the long-term effects of transient DISC-1 gene expression changes near the time of birth in a mouse model. This first study was published in the February 25, 2010 issue of Neuron and has previously been reported on in BioQuick News. Taken together, the results of both studies suggest that anatomical differences that seem to be influenced by the DISC-1 gene cause problems that start before birth, but surface only in young adulthood. “If we can learn more about the cascade of events that lead to these anatomical differences, we may eventually be able to alter the course of schizophrenia. During adolescence, we may be able to intervene to prevent or lessen symptoms,” said second study senior author and first study co-author Dr. Akira Sawa, professor of psychiatry and director of the program in molecular psychiatry at the Johns Hopkins University School of Medicine. Numerous studies have previously suggested that schizophrenia results from abnormal connectivity. The fact that symptoms typically arise soon after adolescence, a time of massive reorganization of connections between nerve cells, supports this idea. The scientists began their second study by surveying rat nerve cells to see where DISC1 was most active. Unsurprisingly, they found the highest DISC-1 activity in connections between nerve cells.
In a finding that overturns conventional wisdom, scientists have reported the first discovery of the female sex hormone progesterone in a plant. Until now, scientists thought that only animals could make progesterone. A steroid hormone secreted by the ovaries, progesterone prepares the uterus for pregnancy and maintains pregnancy. A synthetic version, progestin, is used in birth control pills and other medications. “The significance of the unequivocal identification of progesterone cannot be overstated,” the article, by Dr. Guido F. Pauli and colleagues, claimed. “While the biological role of progesterone has been extensively studied in mammals, the reason for its presence in plants is less apparent.” The authors speculate that the hormone, like other steroid hormones, might be an ancient bioregulator that evolved billions of years ago, before the appearance of modern plants and animals. The new discovery may change scientific understanding of the evolution and function of progesterone in living things. Scientists had previously identified progesterone-like substances in plants and speculated that the hormone itself could exist in plants. But researchers had not found the actual hormone in plants until now. Dr. Pauli and colleagues used two powerful laboratory techniques, nuclear magnetic resonance and mass spectroscopy, to detect progesterone in leaves of the Common Walnut (or English Walnut) tree (Juglans regia). They also identified five new progesterone-related steroids in a plant belonging to the buttercup family. The discoveries were reported online on January 28, 2010 in the American Chemical Society’s Journal of Natural Products. [Press release] [Journal of Natural Products abstract]
A new and comprehensive drug development strategy that starts with extensive screening of potential targeting peptides to rapidly identify prototype small-molecule drugs has produced two that target the EGFR and VEGFR pathways in novel ways, according to a research team led by scientists at The University of Texas M.D. Anderson Cancer Center “The conceptual advance here is to demonstrate how to go rapidly from screening to structural-functional analysis to drug prototype in a few years,” said co-senior author Dr. Wadih Arap, of the David H. Koch Center at M.D. Anderson. “The practical outcome is a pair of new drug candidates, one that acts as a decoy to inhibit a cancer-promoting pathway and another that blocks angiogenesis (the development of new blood vessels), which has the potential to treat both cancer and retinopathies that cause blindness,” said co-senior author Dr. Renata Pasqualini, also of the David H. Koch Center. The group’s approach begins by screening the target receptors with a phage display library used by Drs. Arap and Pasqualini. This method screens billions of viral particles that each display a different peptide on its outer coat to find those that fit into the receptor as a key goes into a lock. Candidate peptides are next winnowed by using structural and functional analysis. Once a peptide is identified and tested, the researchers take an additional step to synthesize a new version of the peptide more suited for use as a drug.
Researchers have successfully used mouse embryonic stem cells to replace diseased retinal cells and restore sight in a mouse model of retinitis pigmentosa. This strategy could potentially become a new treatment for retinitis pigmentosa, a leading cause of blindness that affects approximately one in 3,000 to 4,000 people, or a total of 1.5 million people worldwide. The approach also holds promise for the treatment of other retina-damaging diseases. “This research is promising because we successfully turned stem cells into retinal cells, and these retinal cells restored vision in a mouse model of retinitis pigmentosa,” said Dr. Stephen Tsang, assistant professor of ophthalmology, pathology, and cell biology at Columbia University Medical Center, and lead author of the paper. “The transplanted cells not only looked like retinal cells, but they functioned like them too.” In Dr. Tsang’s study, sight was restored in one-fourth of the mice that received the stem cells. However, complications of benign tumors and retinal detachments were seen in some of the mice, so Dr. Tsang and colleagues will optimize techniques to decrease the incidence of these complications in human embryonic stem cells before testing in human patients can begin. “Once the complication issues are addressed, we believe this technique could become a new therapeutic approach for not only retinitis pigmentosa, but age-related macular degeneration, Stargardt disease, and other forms of retinal disease that also feature loss of retinal cells,” said Dr. Tsang. Specialized retinal cells called the retinal pigment epithelium help maintain vision.
For the first time, researchers have shown that a single-dose HIV DNA vaccine can induce a long-lasting HIV-specific immune response in nonhuman primates, a discovery that could prove significant in the development of HIV vaccines. “Our comprehensive analysis demonstrated for the first time the capacity of a single high dose of HIV DNA vaccine alone to induce long-lasting and polyfunctional T-cell responses in the nonhuman primate model, bringing new insights for the design of future HIV vaccines,” said the researchers from Emory University in the United States and the Institut National de la Recherche Agronomique in France. HIV is persistently spreading at epidemic rates throughout the world, emphasizing the need for a vaccine that can substantially reduce viral loads and minimize transmission. In a previous study, the research team had successfully induced long-lasting and potent HIV-specific immune responses in mice following immunization with a single-dose SHIV DNA-based vaccine. SHIV is a virus that combines genes from HIV in a genetic background of simian immunodeficiency virus (SIV). In the current study, rhesus macaques were immunized with a single high dose of the SHIV DNA-based vaccine and monitored for vaccine-induced immune responses. Results showed that all immunized monkeys developed broad HIV-specific T-cell immune responses that persisted for months. The researchers detailed their findings in the February 2010 issue of the Journal of Virology. [Press release] [J. Virology abstract]
Recognizing faces is an important social skill, but not all of us are equally good at it. Some people are unable to recognize even their closest friends (a condition called prosopagnosia), while others have a near-photographic memory for large numbers of faces. In a recent study of twins, researchers at MIT and in Beijing, China, have shown that face recognition ability is heritable and that it is inherited separately from IQ. This finding plays into a long-standing debate on the nature of mind and intelligence. The prevailing “generalist” theory, upon which the concept of IQ is based, holds that if people are smart in one area they tend to be smart in other areas. So if you are good in math, you are also more likely to be good at literature and history. IQ is strongly influenced by heredity, suggesting the existence of “generalist genes” for cognition. Yet some cognitive abilities seem distinct from overall IQ, as happens when a person who is brilliant with numbers or music is tone-deaf socially or linguistically. Also, many specialized cognitive skills, including recognizing faces, appear to be localized to specialized brain regions. Such evidence supports a “modularity” hypothesis, in which the mind is like a Swiss Army knife–a general-purpose tool with special-purpose devices. “Our study provides the first evidence supporting the modularity hypothesis from a genetic perspective,” said senior author Dr. Jia Liu, Professor of Cognitive Neuroscience at Beijing Normal University. “That is, some cognitive abilities, like face recognition, are shaped by specialist genes rather than generalist genes.” “Our finding may help explain why we see such disparities of cognitive abilities within the same person in certain heritable disorders,” added co-author Dr. Nancy Kanwisher of the McGovern Institute for Brain Research at MIT.
The down-regulation of a key gene in the striatum, a region of the brain attacked in Huntington disease (HD), may be a defensive measure taken by striatal cells to try to avoid ultimate destruction in the HD process. The down-regulated gene (CalDAG-GEFI) is normally highly enriched in the striatal cells that are targeted in HD. An MIT research team, together with collaborators, showed that CalDAG-GEFI gene expression is dramatically down-regulated in the brains of individuals with HD, as well as in mouse models of the disease. By following mutant mice for up to nine months, the researchers further showed that this reduction occurred gradually, in parallel with the progression of the disease. These progressive changes suggested that CalDAG-GEFI is likely to play some role in the disease process. The researchers wanted to determine whether the suppression of this gene is part of the death process, or whether it represents part of the brain’s protective response. They found that the latter explanation appears to be true–when the researchers artificially blocked the expression of CalDAG-GEFI, the striatal neurons were protected from damage induced by the mutant huntingtin (Htt) protein. “So the enriched expression of CalDAG-GEFI in the striatum may explain, in part, why striatal neurons are particularly vulnerable to the expression of mutant Htt,” explained first author Dr. Jill Crittenden of the MIT McGovern Institute for Brain Research. “Switching off of the CalDAG-GEFI gene may represent the neuron’s attempt, ultimately unsuccessful, to save itself.” The researchers hope that by understanding the molecular pathway by which neurons are killed, their findings may suggest new strategies for the development of treatments that could slow or even prevent the progression of HD.
Scientists from Johns Hopkins and collaborating institutions have discovered a clue as to how schizophrenia might develop after puberty as the result of genetic influences that occur in early development. In a new study, the researchers have manipulated (knocked down) a known schizophrenia susceptibility gene (DISC-1) in the brains of fetal mice in an attempt to unravel the complex link between prenatal brain development and the maturation of information processing and cognition in adult animals. The scientists showed that a transient reduction of DISC-1 (disrupted in schizophrenia-1) gene expression in the mouse prefrontal cortex just before or after birth led to aberrant changes in adult animals that are associated with schizophrenia–including perturbation of specific dopaminergic brain pathways, disruption of neural circuitry, and severe behavioral abnormalities. These findings are significant because they provide a concrete link between a nonlethal genetic disruption during prenatal brain development and specific abnormalities in adult brain maturation. “Prior to our study, the kinds of neurodevelopmental defects that cause the defined anatomical changes observed in schizophrenia patients–clinical onset 15+ years after birth, psychosis, impaired cognition and information processing, and aberrant dopaminergic neurotransmission–were not clear,” offered Dr. Toshitaka Nabeshima, the senior author of the report. “However, the model in our study represents a majority of these characteristics.” The authors were careful to caution that while their findings shed some light on how early disease-associated events impact adult brain function, manipulation of one gene cannot fully define the complex neuropathology associated with schizophrenia.
Researchers at the Mayo Clinic have found that protein kinase C-iota (PKCi), an oncogene known to be important in colon and lung cancers, is over-produced in pancreatic cancer and is linked to poor patient survival. They also found that genetically inhibiting PKCi in laboratory animals led to a significant decrease in pancreatic tumor growth and spread. The scientists said that their results strongly indicate that PKCi will be an effective target for pancreatic cancer therapy. The discovery is especially encouraging, they said, because an experimental agent that targets PKCi is already being tested in patients at the Mayo Clinic for other indications. “This is the first study to establish a role for PKCi in growth of pancreatic cancer, so it is exciting to know that an agent already exists that targets PKCi which we can now try in preclinical studies,” said the study’s senior investigator, Dr. Nicole Murray, of the Mayo Clinic’s Department of Cancer Biology. The drug, aurothiomalate, which was once used to treat rheumatoid arthritis, is now being tested in a Phase 1 clinical trial in patients with lung cancer at the Mayo Clinic’s sites in Minnesota and Arizona. Based on findings to date, a Phase 2 clinical trial is being planned to combine aurothiomalate with agents targeted at other molecules involved in cancer growth. Dr. Murray stressed that her group’s new study has not yet tested aurothiomalate against pancreatic cancer, but that any treatment that targets this major cancer pathway offers a new avenue for therapy. “This is such a deadly disease. No standard treatment has shown much promise,” she said. “New ideas and fresh, targeted therapies such as this are sorely needed.” Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of less than 5 percent.