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!
Study reveals how bacteria build essential carbon-fixing machinery
09.07.2020 | University of Liverpool
Stress testing 'coral in a box'
09.07.2020 | University of Konstanz
New insight into the spin behavior in an exotic state of matter puts us closer to next-generation spintronic devices
Aside from the deep understanding of the natural world that quantum physics theory offers, scientists worldwide are working tirelessly to bring forth a...
Kiel physics team observed extremely fast electronic changes in real time in a special material class
In physics, they are currently the subject of intensive research; in electronics, they could enable completely new functions. So-called topological materials...
Solar cells based on perovskite compounds could soon make electricity generation from sunlight even more efficient and cheaper. The laboratory efficiency of these perovskite solar cells already exceeds that of the well-known silicon solar cells. An international team led by Stefan Weber from the Max Planck Institute for Polymer Research (MPI-P) in Mainz has found microscopic structures in perovskite crystals that can guide the charge transport in the solar cell. Clever alignment of these "electron highways" could make perovskite solar cells even more powerful.
Solar cells convert sunlight into electricity. During this process, the electrons of the material inside the cell absorb the energy of the light....
Empa researchers have succeeded in applying aerogels to microelectronics: Aerogels based on cellulose nanofibers can effectively shield electromagnetic radiation over a wide frequency range – and they are unrivalled in terms of weight.
Electric motors and electronic devices generate electromagnetic fields that sometimes have to be shielded in order not to affect neighboring electronic...
A promising operating mode for the plasma of a future power plant has been developed at the ASDEX Upgrade fusion device at Max Planck Institute for Plasma...
07.07.2020 | Event News
02.07.2020 | Event News
19.05.2020 | Event News
09.07.2020 | Physics and Astronomy
09.07.2020 | Power and Electrical Engineering
09.07.2020 | Physics and Astronomy