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 Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH

nachricht Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>