Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

RSRF-Funded Research Links Rett Syndrome to Mitochondrial Gene

26.06.2006
New research from the lab of Adrian Bird, a molecular geneticist at the University of Edinburgh, Scotland, reveals that abnormally high levels of a protein called Uqcrc1 in the brains of mouse models of Rett Syndrome cause mitochondria---the cells' powerhouses--to work overtime. "This is the first time a mitochondrial gene has been linked to Rett Syndrome," says Dr. Bird. Co-author Skirmantas Kriaucionis, now at Rockefeller University in New York City, hopes the finding will lead to treatments for the disorder. "Knowledge of specific physiological defects will, in the future, provide targets for therapeutic intervention," he adds. This research, which was funded in part by the Rett Syndrome Research Foundation, appears in the July issue of the journal Molecular and Cellular Biology.

Rett Syndrome (RTT), a devastating neurological disorder, strikes 1 in 10,000 young children, almost all of them girls. In fact, RTT is the leading genetic cause of severe impairment in girls. Symptoms include neuromuscular problems, autonomic dysregulation, seizures and seizure-like episodes, stereotypical hand movements and the inability to speak. Many children are wheelchair-bound, scoliosis is common, and though the majority live to adulthood, they require total care for every aspect of life.

RTT, which is an autism-spectrum disorder, is caused by mutations in a gene called MECP2. Previous research has shown that the protein made by MECP2 is a master controller of other genes, turning them on and off, and scientists have been searching for these genes. Several have been identified, the best known being brain-derived neurotrophic factor, or BDNF, which normally promotes neuronal growth. To find other genes that MECP2 controls, Bird, Kriaucionis, and other colleagues turned to male mice in which MECP2 has been "knocked out", meaning they lack the protein completely. These animals are born healthy but begin to walk and breathe abnormally around 6 weeks of age, and start dying off at about 10 weeks (the average lifespan of a mouse is 2 years). The team compared the mutant mice to normal mice in search of genes that were off when they should be on, or vice-versa.

First, Kriaucionis purified the messenger RNA made by about 10,000 different genes from the brains of mutant mice that were almost 10 weeks old. Compared to normal animals of the same age, the team found more RNA produced by seven genes and less RNA made by three. Then Kriaucionis examined the messenger RNA produced by those 10 genes in the brains of mice that had only just started coming down with symptoms, at about 7 to 8 weeks of age. Three of the genes made too much of their protein product in the mutant brains as compared to normal brains.

The team reasoned that these three genes played greater roles in the disorder because they went awry earliest. They decided to focus on Uqcrc1 because much was already known about it, including its role in the mitochondria generating energy.

Mitochondria make energy in four steps, and researchers can test to determine which step malfunctions. The team purified mitochondria from the brains of mice lacking Mecp2 and normal mice. They fed energy precursors to the mitochondria and measured how much energy the factories put out.

Uqcrc1 protein works at the third step in the chain, called complex III. If the researchers supplied precursors that are used by mitochondria before the third step, the mitochondria from the mutant animals made significantly more energy than the normal mitochondria. If they supplied precursors that are used after complex III, the mutant mitochondria made the same amount of energy as normal organelles.

This suggested that overabundance of Uqcrc1 in complex III resulted in mitochondria cranking out more energy than the mutant animals needed. "More sounds better but it isn't necessarily that way," says Bird. "Mitochondria are exquisitely regulated machines, so any deviation from normality is likely to be bad."

To find out if Uqcrc1 was to blame for the mitochondrial defects, the team overproduced the protein in cultured neuronal cells. They isolated mitochondria and repeated the energy production tests. The mitochondria from the cultured cells behaved like the mutant brain mitochondria. "What we wanted to know is if the overexpression of this gene was solely responsible for the overactive mitochondria. And the data said it's likely to be," says Bird. He adds that additional experiments are needed to link the mitochondrial abnormalities to the symptoms found in the mutant mice. The researchers also caution that similar defects need to be looked for in humans.

"Our findings provide a mechanism for how a mutation in MECP2 could result in abnormal mitochondrial function," says Kriaucionis.

"I'm very excited about this paper," says Bruce Cohen, a pediatric neurologist who specializes in mitochondrial diseases at the Cleveland Clinic in Cleveland, Ohio. Dr. Cohen, who did not take part in the work, says it validates the suspicions of a few researchers who have argued that malfunctioning mitochondria play a role in the disorder.

"For over 15 years there have been clinical reports of mitochondrial abnormalities in Rett Syndrome patients. Dr. Bird's research provides the first genetic link between MECP2 and mitochondria," states Monica Coenraads, Director of Research for RSRF.

Founded in late 1999, RSRF is the world's largest private source of funds for biomedical research for RTT. For more information on RTT or the Foundation please visit our website at www.rsrf.org.

Monica Coenraads | EurekAlert!
Further information:
http://www.rsrf.org

More articles from Health and Medicine:

nachricht Satellites, airport visibility readings shed light on troops' exposure to air pollution
09.12.2016 | Veterans Affairs Research Communications

nachricht Oxygen can wake up dormant bacteria for antibiotic attacks
08.12.2016 | Penn State

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>