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 Cholesterol-lowering drugs may fight infectious disease
22.08.2017 | Duke University

nachricht Once invincible superbug squashed by 'superteam' of antibiotics
22.08.2017 | University at Buffalo

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: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>