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Archive - Apr 8, 2015

MIT & Whitehead Researchers ID Metabolic Weakness in Subset of Glioblastoma Cells; May Be New Therapeutic Target

Biologists at MIT and the Whitehead Institute for Biomedical Research have discovered a vulnerability of brain cancer cells that could be exploited to develop more-effective drugs against brain tumors. The study, led by researchers from the Whitehead Institute and MIT’s Koch Institute for Integrative Cancer Research, found that a subset of glioblastoma tumor cells is dependent on a particular enzyme (glycine decarboxylase, GLDC) that breaks down the amino acid glycine. Without this enzyme, toxic metabolic byproducts build up inside the tumor cells, and they die. Blocking this enzyme in glioblastoma cells could offer a new way to combat such tumors, says Dr. Dohoon Kim, a postdoc at the Whitehead Institute and lead author of the study, which was published online on April 8, 2015 in Nature. Dr. David Sabatini, a Professor of Biology at MIT and member of the Whitehead Institute, is the paper’s senior author. Dr. Matthew Vander Heiden, the Eisen and Chang Career Development Associate Professor of Biology and a member of the Koch Institute, also contributed to the research, along with members of his lab. GLDC caught the researchers’ attention as they investigated diseases known as “inborn errors of metabolism,” which occur when cells are missing certain metabolic enzymes. Many of these disorders specifically affect brain development; the most common of these is phenylketonuria, marked by an inability to break down the amino acid phenylalanine. Such patients must avoid eating phenylalanine to prevent problems such as intellectual disability and seizures. Loss of GLDC produces a disorder called nonketotic hyperglycinemia, which causes glycine to build up in the brain and can lead to severe mental retardation. GLDC is also often overactive in certain cells of glioblastoma, the most common and most aggressive type of brain tumor found in humans.

Clearer Understanding of DNA Replication Origin Recognition Complex (ORC), As Well As Related Meier-Gorlin Genetic Dwarfism Syndrome Offered by Atomic-Level Resolution Analysis of ORC Crystal Structure

A clearer understanding of the origin recognition complex (ORC) - a protein complex that directs DNA replication - through its crystal structure offers new insight into fundamental mechanisms of DNA replication initiation. This will also provide insight into how ORC may be compromised in a subset of patients with Meier-Gorlin syndrome, a form of dwarfism in humans. ORC is a six-subunit protein complex that directly binds DNA to recruit other protein factors involved in DNA replication. Researchers collected data at the Advanced Photon Source (APS), a U.S. Department of Energy User Facility based at Argonne National Laboratory in Illinois, to obtain the first atomic-level resolution picture of this complex. The structure shows that ORC's main body has five subunits that contain a common fold that is found in proteins binding ATP, a small molecule that cells use as fuel. One of the largest subunits, ORC3, has a structural element that protrudes from the ORC core to contact ORC6, according to the paper, "Crystal Structure of the Eukaryotic Origin Recognition Complex," which was published in the March 19, 2015 issue of in Nature. "The crystal structure explains why a mutation in ORC6 that is linked to Meier-Gorlin syndrome in a subset of patients results in defective binding of this subunit to ORC3," said Dr. Franziska Bleichert, the paper's lead author. "The structure also makes specific predictions on how the different ORC protein subunits might interact with DNA in the central channel of ORC and with other replication initiation factors."

Using Synchrotron, Japanese Scientists Identify Unique Structure of Two Key Receptors (AdipoR1 and AdipoR2) Intimately Related to Obesity and Diabetes; Targeted Drugs May Have Future Impact

A collaboration led by Dr. Shigeyuki Yokoyama of RIKEN and Dr. Takashi Kadowaki and Dr. Toshimasa Yamauchi of the University of Tokyo has used the SPring-8 synchrotron facility (photo) in Harima, Japan to elucidate the structure of two receptors for adiponectin, a protein that is associated with obesity and diabetes. The researchers hope that in the future this work, which was published in Nature on April 8, 2015, will pave the way toward designing drugs that target these two receptors, AdipoR1 and AdipoR2, to reduce the early mortality associated with diabetes. Adiponectin, a hormone secreted by fat cells, is known to be involved in the regulation of glucose and fatty acid oxidation. Its levels are reduced in patients with both type 1 and type 2 diabetes, and giving the hormone to mice has been reported to improve glucose intolerance. In addition, administration of a recently discovered adiponectin receptor agonist, AdipoRon, to genetically obese mice led to improved glucose intolerance and longer lifespans. Because adiponectin binds to two receptors, AdipoR1 and AdipoR2, Dr. Yokoyama, who leads the RIKEN Structural Biology Laboratory, and his team surmised that understanding how this binding takes place could contribute to the creation of drugs that target these receptors. Adiponectin receptors are evolutionarily conserved in many living beings, including mammals, plants, and yeasts, so it seemed clear that these molecules should play important biological role(s). Using the microfocus beamline at the SPring-8 synchrotron facility, the group obtained crystallographic images of the two receptors at resolutions of just 2.9 and 2.4 angstroms, and came up with a surprising finding.

TSRI Scientists Create Model of LPA-Induced Schizophrenia-Like Symptoms in Developing Female Mice

Scientists at The Scripps Research Institute (TSRI) in La Jolla, California have identified a molecule in the brain that triggers schizophrenia-like behaviors, brain changes, and gene expression alterations in an animal model. The research may give scientists new tools for someday preventing or treating psychiatric disorders such as schizophrenia, bipolar disorder, and autism. “This new model speaks to how schizophrenia could arise before birth and identifies possible novel drug targets,” said Dr. Jerold Chun, a Professor and member of the Dorris Neuroscience Center at TSRI who was senior author of the new study. The findings were published online on April 7, 2014 in an open-access article in Translational Psychiatry. The article is titled “LPA Signaling Initiates Schizophrenia-Like Brain and Behavioral Changes in a Mouse Model of Prenatal Brain Hemorrhage.” According to the World Health Organization, more than 21 million people worldwide suffer from schizophrenia, a severe psychiatric disorder that can cause delusions and hallucinations and lead to increased risk of suicide. Although psychiatric disorders have a genetic component, it is known that environmental factors can also contribute to disease risk. There is an especially strong link between psychiatric disorders and complications during gestation or birth, such as prenatal bleeding, low oxygen, or malnutrition of the mother during pregnancy. In this new study, the researchers studied one particular known risk factor: bleeding in the brain, called fetal cerebral hemorrhage, which can occur in utero and in premature babies and can be detected via ultrasound. In particular, the researchers wanted to examine the role of a lipid called lysophosphatidic acid (LPA), which is produced during hemorrhaging.