Researchers find controlling element of Huntington's disease

Huntington's disease, also known as Huntington's chorea, is a hereditary brain disease causing movement disorders and dementia. In Germany, there are about 8,000 patients affected by Huntington's disease, with several hundred new cases arising every year. The disease usually manifests between the ages of 35 and 50. To date, it is incurable and inevitably leads to death. It is caused by a specific genetic defect: In the patient's DNA, which is the carrier of genetic information, there are multiple copies of a certain motif. "Repeats like this are also found in healthy people. However, in cases of Huntington's disease, these sequences are longer than usual," explains Dr. Sybille Krauss from the DZNE in Bonn.

The long DNA sequences in Huntington's disease lead to changes in a certain protein called "Huntingtin". The DNA is like an archive of blueprints for proteins. Errors in the DNA therefore result in defective proteins. "Huntingtin is essential for the organism's survival. It is a multi-talent which is important for many processes," emphasises Krauss. "If the protein is defective, brain cells may die."

In the spotlight: protein synthesis

In the current study, the scientists around Sybille Krauss and the Mainz-based human geneticist Susann Schweiger took a closer look at a critical stage of protein production – translation. At this step, a copy of the DNA, the so-called messenger RNA, is processed by the cell's protein factories. In patients with Huntington's disease, the messenger RNA contains an unusually high number of consecutive CAG sequences – CAG representing the building plan for the amino acid glutamine.

These repetitive sequences have a direct consequence: more glutamine than normal is built into Huntingtin, which is therefore defective. Sybille Krauss and her colleagues have now identified a group of three molecules, which regulate the production of this protein. "We were able to show that this complex binds to the messenger RNA and controls the synthesis of defective Huntingtin," says Krauss. When the scientists reduced the concentration of this so-called MID1 complex in the cell, production of the defective protein declined.

"If we could find a way of influencing this complex, for example with pharmaceuticals, it is quite possible that we could directly affect the production of defective Huntingtin. This kind of treatment would not just treat the symptoms but also the causes of Huntington's disease," says Krauss.

Background:

Three molecules come together

The complex consists of MID1, from which it gets its name, and the proteins PP2Ac and S6K. "Every single one of these proteins is known to be important for translation. We have discovered that in the specific case of Huntington's disease, they together bind to the CAG sequences. This was previously unknown. We also found that binding increases with repeat lengths," says Krauss. "In sequences of normal length, we found only weak binding or none at all."