'Diseases of synapses' demo'd in a dish -- NIH-funded study
Researchers have long suspected that major mental disorders are genetically-rooted diseases of synapses – the connections between neurons. Now, investigators supported in part by the National Institutes of Health have demonstrated in patients' cells how a rare mutation in a suspect gene disrupts the turning on and off of dozens of other genes underlying these connections.
"Our results illustrate how genetic risk, abnormal brain development and synapse dysfunction can corrupt brain circuitry at the cellular level in complex psychiatric disorders," explained Hongjun Song, Ph.D. , of Johns Hopkins University, Baltimore, a grantee of the NIH's National Institute of Mental Health (NIMH), a funder of the study.
Song and colleagues, from universities in the United States, China, and Japan, report on their discovery in the journal Nature, August 18, 2014.
"The approach used in this study serves as a model for linking genetic clues to brain development," said NIMH director Thomas R. Insel, M.D.
Most major mental disorders, such as schizophrenia, are thought to be caused by a complex interplay of multiple genes and environmental factors. However, studying rare cases of a single disease-linked gene that runs in a family can provide shortcuts to discovery. Decades ago, researchers traced a high prevalence of schizophrenia and other major mental disorders – which often overlap genetically – in a Scottish clan to mutations in the gene DISC1 (Disrupted In Schizophrenia-1). But until now, most of what's known about cellular effects of such DISC1 mutations has come from studies in the rodent brain.
To learn how human neurons are affected, Song's team used a disease-in-a-dish technology called induced pluripotent stem cells (iPSCs). A patient's skin cells are first induced to revert to stem cells. Stem cells play a critical role in development of the organism by transforming into the entire range of specialized cells which make up an adult. In this experiment, these particular "reverted" stem cells were coaxed to differentiate into neurons, which could be studied developing and interacting in a petri dish. This makes it possible to pinpoint, for example, how a particular patient's mutation might impair synapses. Song and colleagues studied iPSCs from four members of an American family affected by DISC1-linked schizophrenia and genetically related mental disorders.
Strikingly, iPSC-induced neurons, of a type found in front brain areas implicated in psychosis, expressed 80 percent less of the protein made by the DISC1 gene in family members with the mutation, compared to members without the mutation. These mutant neurons showed deficient cellular machinery for communicating with other neurons at synapses.
The researchers traced these deficits to errant expression of genes known to be involved in synaptic transmission, brain development, and key extensions of neurons where synapses are located. Among these abnormally expressed genes were 89 previously linked to schizophrenia, bipolar disorder, depression, and other major mental disorders. This was surprising, as DISC1's role as a hub that regulates expression of many genes implicated in mental disorders had not previously been appreciated, say the researchers.
The clincher came when researchers experimentally produced the synapse deficits by genetically engineering the DISC1 mutation into otherwise normal iPSC neurons – and, conversely, corrected the synapse deficits in DISC1 mutant iPSC neurons by genetically engineering a fully functional DISC1 gene into them. This established that the DISC1 mutation, was, indeed the cause of the deficits.
The results suggest a common disease mechanism in major mental illnesses that integrates genetic risk, aberrant neurodevelopment, and synapse dysfunction. The overall approach may hold promise for testing potential treatments to correct synaptic deficits, say the researchers.
Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, Kim N-S, Yoon K-J, Shin J, Zhang C, Makri G, Nauen D, Yu H, Guzman E, Chiang C-H, Yoritomo N, Kaibuchi K, Zou J, Christian KM, Cheng L, Ross CA, Margolis RL, Chen G, Kosik KS, Song H, Ming G-l. Synaptic dysregulation in a human iPS cell model of major mental disorders. Nature, Aug. 17, 2014.
About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
Jules Asher | Eurek Alert!
Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden
The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Life Sciences
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy