Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Cell contents may be key to controlling toxicity of Huntington's disease protein

New research into the cell-damaging effects of Huntington's disease suggests a potentially new approach for identifying possible therapeutic targets for treating the nerve-destroying disorder.

Huntington's disease causes the progressive breakdown of nerve cells in the brain and affects an individual's movement, cognition and mental state. Genetically, the disease is associated with a mutation in the Huntingtin gene that causes the huntingtin protein to be produced with an extended region containing the amino acid glutamine.

This is an image showing sequestration of the prion form of translation release factor Sup35 (red) by polyglutamines in an aggresome (green). A new study found that aggresome formation in yeast cells containing Sup35 did not reduce the toxicity of huntingtin proteins with a polyglutamine tract. The study suggests a potentially new approach for identifying possible therapeutic targets for treating Huntington’s disease. Credit: Georgia Tech/Yury Chernoff

The mechanisms that control the severity and onset of the disease are poorly understood, as individuals with the same amount of expansion in their huntingtin proteins experience differences in toxicity and onset of the disease.

A new study led by Georgia Institute of Technology researchers suggests that the toxic effects of the huntingtin protein on cells may not be driven exclusively by the length of the protein's expansion, but also by which other proteins are present in the cell.

The researchers placed human huntingtin protein with an expanded region, called a polyglutamine tract, into yeast cells and found toxicity differences that were based on the other protein aggregates -- called prions -- present in the cells.

"This study clarifies genetic and epigenetic mechanisms that modulate polyglutamine's toxicity on cells and establishes a new approach for identifying potential therapeutic targets through characterization of pre-existing proteins in the cell," said Yury Chernoff, a professor in the School of Biology at Georgia Tech. "While this study was conducted in yeast, it is possible that there are differences in aggregated proteins present in human cells as well, which are causing variation in huntingtin toxicity among individuals."

The results of the study were published in the April 2012 issue of the journal PLoS Genetics. This work was supported by the National Institutes of Health and the Hereditary Disease Foundation.

Also contributing to this research were former Georgia Tech graduate student He Gong and postdoctoral fellow Nina Romanova, University of North Carolina at Chapel Hill School of Medicine research assistant professor Piotr Mieczkowski, and Boston University School of Medicine professor Michael Sherman.

Expanded huntingtin forms clumps in human cells that are typically transported and stored in an internal compartment called an aggresome until they can be removed from the body. While the compartment is thought to protect the contents of the cell from the toxic contents inside the aggresome, the current study shows that huntingtin molecules inside an aggresome can still be toxic to the cell.

In the study, aggresome formation in the cells containing the prion form of the Rnq1 protein reduced the toxicity of the huntingtin protein in Saccharomyces cerevisiae yeast cells, whereas the huntingtin protein's toxicity remained in the presence of the prion form of translation release factor Sup35.

"It remains uncertain whether the toxicity was primarily driven by sequestration of Sup35 into the aggresome or by its sequestration into the smaller huntingtin protein aggregates that remained in the cytoplasm," explained Chernoff, who is also director of the Center for Nanobiology of the Macromolecular Assembly Disorders (NanoMAD). "While Sup35 was detected in the aggresome, we don't know if the functional fraction of Sup35 was sequestered there."

In a follow-on experiment, the researchers increased the level of another release factor, Sup45, in the presence of Sup35 and found that this combination counteracted the toxicity.

"While the Rnq1 and Sup35 prions did not cause significant toxicity on their own, the results show that prion composition in the cell drove toxicity," noted Chernoff. "Prions modulated which proteins were sequestered by the aggresome, as proteins associated with the pre-existing prions were more likely to be sequestered, such as Sup45 because of its association with Sup35."

It remains unknown if polyglutamines can sequester the human versions of the Sup35 and Sup45 release factors, but this study shows the possibility that organisms may differ by the protein composition in their cells, and this in turn may influence their susceptibility to polyglutamine disorders such as Huntington's disease.

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under award numbers GM058763, GM093294 and GM086890. The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NIH.

Abby Robinson | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Signaling Pathways to the Nucleus
19.03.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht In monogamous species, a compatible partner is more important than an ornamented one
19.03.2018 | Max-Planck-Institut für Ornithologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Tiny implants for cells are functional in vivo

For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...

Im Focus: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

Im Focus: Surveying the Arctic: Tracking down carbon particles

Researchers embark on aerial campaign over Northeast Greenland

On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...

Im Focus: Unique Insights into the Antarctic Ice Shelf System

Data collected on ocean-ice interactions in the little-researched regions of the far south

The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...

Im Focus: ILA 2018: Laser alternative to hexavalent chromium coating

At the 2018 ILA Berlin Air Show from April 25–29, the Fraunhofer Institute for Laser Technology ILT is showcasing extreme high-speed Laser Material Deposition (EHLA): A video documents how for metal components that are highly loaded, EHLA has already proved itself as an alternative to hard chrome plating, which is now allowed only under special conditions.

When the EU restricted the use of hexavalent chromium compounds to special applications requiring authorization, the move prompted a rethink in the surface...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

Latest News

A new kind of quantum bits in two dimensions

19.03.2018 | Physics and Astronomy

Scientists have a new way to gauge the growth of nanowires

19.03.2018 | Materials Sciences

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Science & Research
Overview of more VideoLinks >>>