Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

As the Protein Folds: The Tail of the Gene Tells the Tale of Machado-Joseph Disease

01.04.2005


The repetition of three little "letters" within the gene that codes for the ataxin-3 protein is both the cause of and perhaps a solution to Machado-Joseph disease and an entire family of similar genetic disorders, according to researchers at the University of Pennsylvania. Their findings, which appear today in the journal Molecular Cell, present a potential therapeutic role for the ataxin-3 protein for MJD and related disorders such as Huntington’s disease.



Machado-Joseph disease is among the most common of the nine known polyglutamine repeat disorders, a family of diseases in which the genetic code for the amino acid polyglutamine CAG becomes excessively repeated within the gene, making the protein toxic. In these diseases, the expanded polyglutamine domain causes the errant protein to fold improperly, which causes a glut of misfolded protein to collect in tissues of the nervous system, much like what occurs in Alzheimer’s and Parkinson’s diseases.

"In origami, if you misfold the paper, you can just throw the paper into the recycling bin," said Nancy Bonini, a Penn professor of biology and Howard Hughes Medical Institute investigator. "If a protein misfolds, cells rely on their own recycling system to dispose of it. It turns out that ataxin-3 may influence this system, especially for recycling those that have misfolded due to excessive polyglutamine repeats.. Our findings show that ataxin-3 not only blunts the toxicity of mutant versions of itself but can also mitigate neurodegeneration induced by other such mutant polyglutamine proteins."


Machado-Joseph disease is among the most common dominantly inherited ataxias, a neurodegenerative disorder marked by a gradual decay of muscle control. MJD typically appears in adulthood, with a longer repeat expansion being associated with earlier onset and more severe disease. Its symptoms, uncoordinated motor control, worsen with time.

To study just how the ataxin-3 protein relates to disease, Bonini and her colleagues worked in a simple model organism, the fruit fly, engineering flies to express both the normal human ataxin-3 protein (the protein encoded by the SCA3 gene) and a toxic human disease form of ataxin-3 with an expanded polyglutamine repeat. When both genes are in the same fruit fly, however, the functioning gene helps protect against the effects of the bad one. Their studies surprisingly demonstrated that the protective function of the ataxin-3 protein does not rely on the multiple repeats in its tail but in a region near the head. Indeed, it seems that removing or altering this region of the gene can accelerate the progress of the disease.

"The secret of ataxin-3 is that regions near the start of the protein can counterbalance the toxicity conferred by the excessive polyglutamine repeats in the mutant protein," Bonini said. "In fact, we found evidence that mutant ataxin-3 with the extra-long polyglutamine tail can mitigate its own toxicity."

According to the researchers, it may explain why even normal ataxin-3 can have multiple CAG repeats without causing disease. In other polyglutamine diseases, mutant genes with far fewer repeats can still be toxic, whereas ataxin-3 disease mutations are generally associated with much longer repeats.

"One question now is how this information can be used clinically," Bonini said. "While more research needs to be done, we are hopeful that ataxin-3 may prevent the protein accumulation associated with polyglutamine diseases and perhaps other neurodegenerative situations as well."

Researchers whose work contributed to this study are John M. Warrick (now of the University of Richmond), Lance Morabito, Julide Bilen, Beth Gordesky-Gold and Lynn Faust of Penn, and Henry L. Paulson of the University of Iowa.

Funding for this study was provided by the National Institutes of Health, the David and Lucile Packard Foundation and the Howard Hughes Medical Institute.

Greg Lester | EurekAlert!
Further information:
http://www.upenn.edu

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

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

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>