Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Of yeast and men: Unraveling the molecular mechanisms of Friedreich's ataxia

13.07.2009
Researchers in human genetics have long known that expansions of GAA repeats – resulting in this nucleotide triplet repeating hundreds or thousands of times – cause the most common hereditary neurological disorder known as Friedreich's ataxia. There is no cure for this condition, which damages the nervous system and can result in heart disease.

The disease's origins have been proven through analysis of genetic records of affected individuals and their families. But scientists have not been able to study the molecular processes that cause the GAA sequence to expand so profoundly because they have lacked a model that could produce the large-scale expansions for experimental purposes.

In a paper to be published in the July issue of "Molecular Cell," a research team lead by Sergei Mirkin, White Family Professor of Biology at Tufts' School of Arts and Sciences, has created an experimental model that does indeed produce large-scale expansion of GAA repeats during DNA replication.

In doing so, Mirkin and his team were able to analyze GAA repeat expansions and then identify cellular proteins that thwarted normal replication and promoted the elongated sequence.

"In essence we believe that the replication machinery occasionally gets tangled within a repetitive run, adding extra repeats while trying to escape," says Mirkin. "And the longer the repeat - the more likely the entanglement is. That is as if a car which entered a roundabout misses the right exit due the heavy traffic and has to make the whole extra circle before finally escaping."

The researchers started with common baker's yeast because it allowed them to monitor the progress and genetic control of repeat expansions, which is not feasible in humans.

When they inserted GAA repeats of varying lengths (50-to-150 triplet repeats) into an intron of the specifically modified reporter gene they found that widespread expansions of these repeats indeed occurred. These expansions blocked RNA splicing and, as a result, deactivated the gene.

This allowed the team to measure the precise rate of repeat expansions at various experimental settings by growing yeast on the special selective medium followed by determining the repeat lengths via polymerase chain reaction.

Using this approach, the researchers observed massive expansion of GAA repeats that ranged between 200 and 450 repeats. Remarkably, they found that the likelihood of a repeat expansion increased as it grew longer, which closely mimicked the situation observed in the genetic record of humans with Friedreich's ataxia.

Mirkin and his team then carried out a genetic screen to identify yeast proteins affecting repeat expansions. They found that the proteins within the cell that are known to facilitate the smooth replication fork progression decreased repeat expansions. Meanwhile the proteins responsible for the fork deviations, such as template switching and reversal, increased repeat expansions.

Mirkin's research is funded by the National Institutes of Health. Mirkin's team included Tufts postdoctoral fellow Alexander A. Shishkin; graduate student Irina Voineagu and Brook T. Chernot; undergraduates Robert Matera, Nicole Cherng and former laboratory member Maria M. Krasilnikova, who is currently on the faculty of Penn State. Collaborators also included Georgia Tech Professor Kirill Lobachev and postdoctoral fellow Vydhia Narayanam.

Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

Alex Reid | EurekAlert!
Further information:
http://www.tufts.edu

More articles from Life Sciences:

nachricht Designer cells: artificial enzyme can activate a gene switch
22.05.2018 | Universität Basel

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

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

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...

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

Designer cells: artificial enzyme can activate a gene switch

22.05.2018 | Life Sciences

PR of MCC: Carbon removal from atmosphere unavoidable for 1.5 degree target

22.05.2018 | Earth Sciences

Achema 2018: New camera system monitors distillation and helps save energy

22.05.2018 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>