Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Suspect Gene Corrupts Neural Connections

Published: Tuesday, August 19, 2014
Last Updated: Monday, August 18, 2014
Bookmark and Share
“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. External Web Site Policy, 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.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Study Shows Promise of Precision Medicine for Most Common Type of Lymphoma
The study appeared online July 20, 2015, in Nature Medicine.
Tuesday, July 21, 2015
NIH Study Identifies Gene Variant Linked to Compulsive Drinking
Mice carrying the Met68BDNF gene variant would consume excessive amounts of alcohol.
Tuesday, July 21, 2015
In Blinding Eye Disease, Trash-Collecting Cells Go Awry, Accelerate Damage
NIH research points to microglia as potential therapeutic target in retinitis pigmentosa.
Friday, July 03, 2015
Potential Therapeutic for Blinding Eye Disease
NIH research points to microglia as potential therapeutic target in retinitis pigmentosa.
Thursday, July 02, 2015
NCI-MATCH Trial will Link Targeted Cancer Drugs to Gene Abnormalities
Precision medicine trial will open to patient enrollment in July.
Tuesday, June 09, 2015
A New Role for Zebrafish: Larger Scale Gene Function Studies
A relatively new method of targeting specific DNA sequences in zebrafish could dramatically accelerate the discovery of gene function and the identification of disease genes in humans.
Monday, June 08, 2015
NIH Researchers Pilot Predictive Medicine by Studying Healthy People’s DNA
New study sequence the genomes of healthy participants to find “putative,” or presumed, mutations.
Friday, June 05, 2015
Linking Targeted Cancer Drugs to Gene Abnormalities
Investigators at the NIH have announced a series of clinical trials that will study drugs or drug combinations that target specific genetic mutations.
Wednesday, June 03, 2015
Scientists Create Mice with a Major Genetic Cause of ALS and FTD
NIH-funded study provides new platform for testing treatments for several neurodegenerative disorders.
Friday, May 22, 2015
Mice With a Major Genetic Cause of ALS and FTD Created
NIH-funded study provides new platform for testing treatments for several neurodegenerative disorders.
Thursday, May 21, 2015
New Insights into How DNA Differences Influence Gene Activity, Disease Susceptibility
NIH-funded pilot study provides a new resource about variants across the human genome.
Friday, May 08, 2015
Souped-up Remote Control Switches Behaviors On-and-Off in Mice
BRAIN Initiative yields chemical-genetic tool with push-pull capabilities.
Thursday, May 07, 2015
NIH-funded Study Points Way Forward for Retinal Disease Gene Therapy
Benefits for Leber congenital amaurosis peak after one to three years, then diminish.
Tuesday, May 05, 2015
Possible Treatment for Lethal Pediatric Brain Cancer
NIH-funded preclinical study suggests epigenetic drugs may be used to treat leading cause of pediatric brain cancer death.
Tuesday, May 05, 2015
Statement on NIH Funding of Research Using Gene-Editing Technologies in Human Embryos
Researchers modify the gene responsible for a potentially fatal blood disorder using CRISPR/Cas9 technology.
Saturday, May 02, 2015
Scientific News
RNAi Screening Trends
Understand current trends and learn which application areas are expected to gain in popularity over the next few years.
New Tech Enables Epigenomic Analysis with a Mere 100 Cells
A new technology that will dramatically enhance investigations of epigenomes, the machinery that turns on and off genes and a very prominent field of study in diseases such as stem cell differentiation, inflammation and cancer has been developed by researchers at Virginia Tech.
Access Denied: Leukemia Thwarted by Cutting Off Link to Environmental Support
A new study reveals a protein’s critical – and previously unknown -- role in the development and progression of acute myeloid leukemia (AML), a fast-growing and extremely difficult-to-treat blood cancer.
New Weapon in the Fight Against Blood Cancer
This strategy, which uses patients’ own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable.
Toxin from Salmonid Fish has Potential to Treat Cancer
Researchers from the University of Freiburg decode molecular mechanism of fish pathogen.
Study Finds Non-Genetic Cancer Mechanism
Cancer can be caused solely by protein imbalances within cells, a study of ovarian cancer has found.
Scientists Create CRISPR/Cas9 Knock-In Mutations in Human T Cells
In a project spearheaded by investigators at UC San Francisco, scientists have devised a new strategy to precisely modify human T cells using the genome-editing system known as CRISPR/Cas9.
Tracking Breast Cancer Before it Grows
A team of scientists led by University of Saskatchewan researcher Saroj Kumar is using cutting-edge Canadian Light Source techniques to screen and treat breast cancer at its earliest changes.
DNA Damage Seen in Patients Undergoing CT Scanning
Along with the burgeoning use of advanced medical imaging tests over the past decade have come rising public health concerns about possible links between low-dose radiation and cancer.
The Mystery of the Instant Noodle Chromosomes
Researchers from the Lomonosov Moscow State University evaluated the benefits of placing the DNA on the principle of spaghetti.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!