San Diego, California – in a major advance for schizophrenia research, an international team of scientists, led by Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at the University of California, San Diego School of Medicine, has identified a gene mutation strongly linked to the brain disorder - and a signaling pathway that may be treatable with existing compounds.

The work poses significant and immediate implications for neurobiology and the treatment of schizophrenia because the gene identified by the researchers is an especially attractive target for drug development.

“in some ways, this is the kind of gene that the pharmaceutical industry has been waiting for,” said Sebat, who is also chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases and a member of the Institute for Genomic Medicine, both at UC San Diego. “its activity can be modulated by synthetic peptides; and some have already been created.”

Schizophrenia is a chronic, severe and disabling brain disorder, with symptoms that include hallucinations, delusions and thought disorders. it is believed to be caused by environmental and genetic factors, most notably the latter: the illness occurs in 1 percent of the general population, or 10 percent of people who have a first-degree relative with the disorder, such as a parent or sibling.

In previous work, Sebat and collaborator Mary-Claire King, a professor of medical genetics at the University of Washington, discovered that rare mutations at many locations in the human genome resulted in significantly higher risk of schizophrenia. these mutations consisted of copy number variants or CNVs – a type of genetic variation in which the number of copies of a gene differs between individuals. the findings were the first conclusive evidence that rare mutations can cause schizophrenia, but they did not identify the specific genes involved.

The latest study goes much further. Researchers scanned for CNVs in the genomes of 8,290 individuals with diagnosed cases of schizophrenia and 7,431 healthy controls. “We found very strong links to multiple sites in the genome,” said Sebat. “Some had been picked up before in earlier studies, but we uncovered a very important new finding: duplications at the tip of chromosome 7q were detected in individuals with schizophrenia at a rate14 times higher than in healthy individuals. these CNVs impact a gene that is important for brain development – the neuropeptide receptor VIPR2.”

Formally known as the Vasoactive Intestinal Peptide Receptor 2, VIPR2 is expressed in the nervous system, including in the brain, blood vessels and gastrointestinal tract. Previous studies have shown that VIPR2 helps to regulate the formation and activity of neurons in the brain. in mice, VIPR2 also has been found to play important roles in behavioral processes, including learning and timing of daily activity.

Sebat and colleagues measured expression of the VIPR2 gene in blood cells from the patients, and they found that individuals with mutations had greater expression of VIPR2 and greater activity of the receptor. “We concluded that the effect of the causal mutations is to raise the volume on the VIP signaling pathway,” said Sebat.

“this discovery might be the best target yet to come out of genetic studies of mental illness.” said Sebat. “this is what genomic medicine is all about, finding the relevant genes and using this genetic information to come up with a possible strategy for treatment.”

Sebat said the next step will be to test whether compounds like these have beneficial effects in mice and in cultured human cells that carry the VIPR2 gene mutation.

Researchers involved are Vladimir Vacic, Stanley Center for Cognitive Genomics, Cold Spring Harbor Laboratory and the Department of Computer Science, Columbia University; Shane McCarthy, Stanley Center for Cognitive Genomics, Cold Spring Harbor Laboratory; Dheeraj Malhotra, Beyster Center for Genomics of Psychiatric Diseases, UCSD Department of Psychiatry and Stanley Center for Cognitive Genomics, Cold Spring Harbor Laboratory; Fiona Murray, UCSD departments of Medicine and Pharmacology; Hsun-Hua Chou, Beyster Center for Genomics of Psychiatric Diseases and UCSD Department of Psychiatry; Aine Peoples, Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Department of Psychiatry, Trinity College Dublin, Ireland; Vladimir Makarov and Seungtai Yoon, Seaver Autism Center and Department of Psychiatry, Mount Sinai School of Medicine, new York; Abhishek Bhandari, Beyster Center for Genomics of Psychiatric Diseases, UCSD Department of Psychiatry, Stanley Center for Cognitive Genomics, Cold Spring Harbor Laboratory; Roser Corominas and Lilia M. Iakoucheva, UCSD Department of Psychiatry; Olga Krastoshevsky, Verena Krause and Deborah L. Levy, McLean Hospital, Belmont, MA; Verónica Larach-Walters, Universidad Andrés Bello, Santiago, Chile; David K. Welsh, UCSD Department of Psychiatry, UCSD Center for Chronobiology, Veterans Affairs San Diego Healthcare system; David Craig, Neurogenomics Division, Translational Genomics Research Institute; John R. Kelsoe, UCSD Department of Psychiatry, UCSD Institute for Genomic Medicine, Veterans Affairs San Diego Healthcare system; Elliot S. Gershon, Department of Psychiatry and Behavioral Neuroscience, the University of Chicago; Suzanne M. Leal, Department of Molecular and Human Genetics, Baylor College of Medicine; Marie Dell Aquila, UCSD Division of Medical Genetics, UCSD Department of Medicine; Derek W. Morris, Michael Gill and Aiden Corvin, Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Department of Psychiatry, Trinity College Dublin, Ireland; Paul A. Insel, UCSD Department of Pharmacology, Veterans Affairs San Diego Healthcare system; Jon McClellan, Department of Psychiatry, University of Washington; Mary-Claire King, departments of Genome Sciences and Medicine, University of Washington; Maria Karayiorgou, Department of Psychiatry, Columbia University; and Lynn E. DeLisi, Department of Psychiatry, Boston VA Healthcare system and Harvard Medical School.

Funding for this research came, in part, from the Stanley Medical Research Foundation, the Beyster Family Foundation, the National Alliance for Research on Schizophrenia and Depression and the National Institutes of Health.

Posted on: Wednesday, 2 February 2011, 10:45 CST

Swiss researchers develop new, working mammalian model to combat genetic causes of the disease

Evidence is steadily mounting that genetic factors play an important role in many cases of Parkinson’s disease (PD). in a study published February 2, 2011, online in the Journal of Neuroscience, researchers from the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland report a new mammalian model for studying a specific gene mutation commonly found in PD sufferers, opening the door to new drugs to fight the malady.

"This is a great step forward toward a more comprehensive understanding of how the disease works, and how it can be diagnosed and treated," explains neuroscientist and EPFL President Patrick Aebischer, lead author of the study.

PD is a common neurodegenerative disease that greatly reduces quality of life and costs the United States around 23 billion dollars a year. until now, researchers have encountered difficulty in reproducing PD pathology in animals because of an incomplete understanding of the disease.

Recently, a mutation of the gene coding for LRRK2, a large enzyme in the brain, has emerged as the most prevalent genetic cause of PD (genetics are implicated in about 10 percent of all PD cases). when the enzyme is mutated, it becomes hyperactive, causing the death of vulnerable neurons and leading to a reduction in levels of the brain neurotransmistter dopamine. This decrease in dopamine eventually triggers the symptoms characteristic of Parkinson’s, such as tremors, instability, impaired movement, and later stage dementia.

Now, with funding from the Michael J. Fox Foundation for Parkinson’s Research, Aebischer and his team in the Neurodegenerative Studies Laboratory at EPFL, have successfully introduced mutant LRRK2 enzyme into one hemisphere of a rat brain, resulting in the same PD manifestations that occur in humans in one side of the rodent’s body. To do this, the researchers spent two years producing and optimizing a viral vector to deliver mutated, LRRK2 coding DNA into the rat brain. LRRK2 is a large and complicated enzyme and designing a vector capable of transporting its extremely long genetic code was no small feat.

The new animal model developed by EPFL is sure to benefit future Parkinson’s research. the fact that LRRK2 is an enzyme—a catalyzing protein involved in chemical reactions—makes it drug accessible and therefore of specific interest to researchers looking for neuroprotective strategies, or pharmaceutical treatments that halt or slow disease progression by protecting vulnerable neurons. Armed with the LRRK2 model, new pharmaceuticals that inhibit the hyper-activity of the enzyme could one day prevent the destructive chain of events that leads to neurodegeneration and devastation in many with PD.

Image 1: a vector is introduced into the healthy brain cell and transmits the mutated gene. Credit: EPFL

Image 2: This is a cervical slice showing the healthy left-hand side of the brain and the damaged, Parkinson’s disease side with lesions provoked by the LKKR2 gene mutation. Credit: EPFL

On the Net:

• Ecole Polytechnique Fédérale de Lausanne
• Journal of Neuroscience

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