A study recently published in the journal Molecular Cell revealed a new role played by polyglutamine repeats in addition to their link to neurodegenerative disorders. The study is entitled “Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity” and was led by researchers at the Katholieke Universiteit (KU) Leuven and the VIB – Flanders Interuniversity Institute for Biotechnology in Belgium.
An abnormal high number of glutamine-rich repeats in specific human proteins is known to underlie severe neurodegenerative disorders. One of these disorders is Huntington’s disease, a progressive, neurodegenerative, genetic disorder characterized by the lack of muscle coordination, unsteady gait, mental decline and behavioral symptoms. The disease is caused by an expanded CAG triplet repeat in a gene called huntingtin, leading to the production of a mutant huntington protein that accumulates in the brain interfering with its proper functioning.
There is a lack of information concerning the physiological role of polyglutamine repeats and the clinical consequences of a moderate repeat expansion.
Now, researchers have discovered that DNA polyglutamine repeats can modify the function of the protein in which they are present, and tune the development of healthy cells and organisms.
The team used a strain of brewer’s yeast and engineered a range of cells that were identical except for the number of polyglutamine repeats in a gene called Ssn6, which encodes the Ssn6 protein, known to regulate the function of certain genes. Researchers found that incremental changes in the number of repeats did not caused harmful variations in the expression of the genes which are regulated by Ssn6, but that these were rather accompanied by dynamic and gradual changes in the physiology and characteristics of the cell. They suggested that Ssn6 function increases with its polyglutamine repeat number up to a point where further expansion actually leads to aggregation and, in the case of certain genes, the development of serious diseases.
“We found that the polyglutamine repeats act like the dial on a tuner. The length of the repeat modulates the transcriptional response of genes in the cell. More specifically, using a polyglutamine-containing protein called Ssn6 as a model, we showed that the repeat length modulates the solubility of Ssn6 and its interaction with other proteins. When the dial is turned too far and repeats are abnormally expanded — similarly to what happens in polyglutamine diseases — the function of the Ssn6 protein deteriorates. It then no longer interacts properly with its normal partners and aggregates with other proteins, potentially leading to neurodegenerative diseases.” explained the study’s lead author Dr. Rita Gemayel in a news release.
In conclusion, the research team suggests that polyglutamine repeats might not only be potentially harmful elements in the DNA, but they may actually play an important role in controlling cell development and physiology. The authors believe that these findings might be important for the development of novel therapies for human polyglutamine repeat diseases.
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