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.
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 characterisation of pre-existing proteins in the cell," said Doctor Yury Chernoff. "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."
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.
MEDICA.de; Source: Georgia Institute of Technology