Number of CAG Repeats in Mutated Huntingtin Linked to Disease Onset in Study

Number of CAG Repeats in Mutated Huntingtin Linked to Disease Onset in Study
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Huntington’s disease is caused by excessive repeats of a portion of DNA, called CAG triplets, within the gene that codes for huntingtin (HTT). New research shows how the number of CAG repeats determines the final form and the aggregation profile of the resulting protein.

The study, “The Aggregation Free Energy Landscapes of Polyglutamine Repeats,” was published in the Journal of the American Chemical Society.

Each CAG triplet encodes an amino acid (the building blocks of proteins) called glutamine. Several CAG repeats in the HTT gene lead to the production of HTT with more glutamines than normal — polyglutamine HTT — which disrupts the normal workings of the protein. This is why Huntington’s disease is considered a polyglutamine disease.

While healthy individuals may have up to 36 CAG repeats, individuals with more than this number usually develop the disease. Previous studies have suggested that the longer the extension of glutamines in this protein, the earlier and more severe will be the symptoms.

Researchers by Peter Wolynes, with Rice University, investigated how the length of repeats — a minimum of 20 repeats and a maximum of 50 — determined how the protein would aggregate in the cell’s nucleus and lose its normal activity.

“The final form of the protein detected in people who have Huntington’s disease is a macroscopic aggregate made of many molecules, much like an ice crystal formed out of water has many molecules in it,” Wolynes said in a news release. “This process needs to start somewhere, and that would be with a nucleus, the smallest-size cluster that will then be able to finish the process and grow to macroscopic size.

“People knew that the length of the repeats is correlated with the severity of a disease, but we wanted to know why that matters to the critical nucleus size,” he said.

From previous experiments, the team knew that HTT with 20 CAG repeats or less remained unfolded (“noodle-y,” Wolynes said), and would only accumulate in the nucleus when other four or more units of the protein were also present. But HTT sequences with 30 or more repeats or more could incorrectly fold by themselves into the shape of a hairpin, starting the toxic aggregation process.

HTT with intermediate polyglutamine lengths (between 20 and 30 CAG repeats) could either adopt the straight or hairpin forms, the researchers reported.

The analysis also showed that while shorter and longer sequences form aligned fiber bundles, intermediate sequences likely form disordered and branched structures, which scientists do not yet know to be good or bad.

Together, these results help to explain how mutations in the HTT gene influence the resulting protein. Mutations causing a shorter sequence of polyglutamines will lead to the production of a straight form of HTT, whereas mutations causing a longer sequence of polyglutamines will lead to an aggregating protein.

“What’s ironic is that while Huntington’s has been classified as a misfolding disease, it seems to happen because the protein, in the bad case of longer repeats, carries out an extra folding process that it wasn’t supposed to be doing,” Wolynes said.

The team is now investigating how the complete HTT protein, which contains other parts besides the polyglutamine repeats, aggregates.

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