Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Linking Fragile X Syndrome proteins and RNA editing mistakes at nerve-muscle junction

31.10.2011
Penn study in fruit flies has implications for autism, other cognitive impairment syndromes

The most common form of heritable cognitive impairment is Fragile X Syndrome, caused by mutation or malfunction of the FMR1 gene. Loss of FMR1 function is also the most common genetic cause of autism. Understanding how this gene works is vital to finding new treatments to help Fragile X patients and others.

Researchers from the Perelman School of Medicine at the University of Pennsylvania, and colleagues from Brown University, have identified the FMRP protein (encoded by FMR1) as a key player in RNA editing, a process in which the working copies made from DNA, called messenger RNAs, are chemically altered after being transcribed from the genome. Their findings were published online this week in Nature Neuroscience.

Since RNAs are used as the instructions to make proteins, mistakes in RNA editing at the neuromuscular junction (NMJ), the site at which motor neurons innervate muscle, may cause problems in nerve function. Previous work at Penn and several other institutions strongly suggested the role of FMRP to be in regulating the translation of certain types of RNA at the synapse, the space between two nerves, or between nerves and muscles.

"Most of the field has been focused on looking at FMRP interacting with specific RNAs and how it regulates their translation at the synapse," states lead author Thomas A. Jongens, PhD, associate professor of Genetics at Penn. "Here we've tapped into identifying a function that FMRP has in regulating another process called RNA editing that is important in regulating neural activity." In RNA editing, the information encoded by DNA into an RNA molecule is altered, thus affecting the functioning of the proteins encoded by that RNA.

"This work elegantly links the Drosophila FMR1 gene to both an RNA-editing pathway and the architecture of the neuromuscular junction synapse," says Donna Kransnewich, PhD, who oversees grants focused on mechanisms of human genetic disorders at the National Institute of General Medical Sciences of the National Institutes of Health. "These exciting findings bring us closer to understanding the molecular basis of Fragile X syndrome, the most common inherited intellectual disability, and highlight the value of basic science research in uncovering the underlying causes of human disorders."

Lords of the Flies

Jongens, Penn colleague Balpreet Bhogal, and Brown colleague Robert Reenan studied the fruit fly, Drosophila, whose genome contains a cousin of the human FMR1 gene called dFMR1. The Jongens lab is one of several that use Drosophila models to study Fragile X Syndrome.

"The Drosophila dFMR1 gene is fairly similar to that in humans at the amino acid level - there's about a 50 percent overall similarity between the two proteins," Jongens notes. "But if you look at specific domains, there are pockets of even higher similarity. That makes us fairly confident that some of what we'll discover from the fly model translates to people."

Flies with mutated dFMR1 genes exhibit similar physiological symptoms as humans with Fragile X, including memory and cognitive deficits, disrupted sleep and circadian rhythms, and impaired social behavior.

Two Key Proteins

Another impaired trait due to the mutation is overgrowth and branching of the neuromuscular junction. The research group showed that another key protein critical for normal functioning and architecture at the NMJ is ADAR (dADAR in Drosophila), which is involved in RNA editing of specific mRNAs. The researchers examined the Drosophila NMJ to determine whether dFMR1 and dADAR interact.

They found that the right amounts of the two proteins are important for proper RNA editing and therefore nerve activity at the nerve-muscle synapse. Using a variety of genetic and molecular analyses, Jongens and colleagues were able to link dFMR1 with dADAR via the RNA editing required for normal NMJ structure.

Observing that flies with dADAR mutations displayed similar NMJ defects to flies with dFMR1 mutations, the team demonstrated that both the dFMR1 and dADAR proteins act in the motor neuron to form the neuromuscular junction, indicating that ADAR is required for proper NMJ structure.

In addition, says Jongens, "we found that ADAR acts downstream of dFMR1, suggesting that dFMR1 is required to maintain the proper activity levels of ADAR in the synapse. The FMR protein physically associates with the fly ADAR protein, and through genetic studies we see that there's a dependence of ADAR function on FMRP. If you don't have FMRP, or if you have too much, the editing efficiency of certain sites on select mRNAs is changed. So we think that FMRP might play a role - through the editing process - in modulating the fine tuning of neuronal activity."

The work is the first study to report a disease-associated protein that interacts with and modulates RNA editing. "It provides another way in which the Fragile X Syndrome animal models can be examined to look for defects in neuronal processes that might explain symptoms seen in people," Jongens explains.

Reenan, professor of Molecular Biology, Cell Biology and Biochemistry at Brown, agrees, saying that the implications of the study could be quite broad: "It is a remarkable finding that FMRP can be linked so directly with ADAR and RNA editing activity. Deranged RNA editing has been implicated in epilepsy, suicidal depression, schizophrenia, and even some neurological cancers. These data are surely pointing in the direction of deep connections between numerous distinct diseases of the brain."

The next step in the research will focus on how the two proteins come together to act on the same RNA targets. "The more we know about what the FMR protein does, the more likely we are to uncover ways to treat disease," Jongens points out.

The research was funded by the National Institute of Mental Health, the National Institute of General Medical Sciences, and the Ellison Medical Foundation.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.

Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
22.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

Im Focus: Computer-Designed Customized Regenerative Heart Valves

Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.

Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...

Im Focus: Light-induced superconductivity under high pressure

A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.

Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Supersonic waves may help electronics beat the heat

18.05.2018 | Power and Electrical Engineering

Keeping a Close Eye on Ice Loss

18.05.2018 | Information Technology

CrowdWater: An App for Flood Research

18.05.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>