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 Designed proteins to treat muscular dystrophy
29.06.2017 | Universität Basel

nachricht Funding of Collaborative Research Center developing nanomaterials for cancer immunotherapy extended
28.06.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

High conductive foils enabling large area lighting

29.06.2017 | Power and Electrical Engineering

Designed proteins to treat muscular dystrophy

29.06.2017 | Life Sciences

Climate Fluctuations & Non-equilibrium Statistical Mechanics: An Interdisciplinary Dialog

29.06.2017 | Seminars Workshops

VideoLinks
B2B-VideoLinks
More VideoLinks >>>