They reveal the structure of the main protein involved in Huntington’s disease

Huntington’s disease, a severe neurodegenerative disease characterized by progressive impairment of movement and cognitive function, is triggered by a genetic mutation affecting the huntingtin protein. This defect is due to the expansion of the cytosine, adenine and guanine nucleotides, which are responsible for encoding in the DNA the synthesis of glutamine, one of the 20 amino acids involved in the composition of proteins. As a result, the number of glutamines in the protein increases, something that is directly related to the formation of protein aggregates in the brain.

Although the function of the huntingtin protein is unknown, until now it is known that it is involved in neurological development and that a minimum number of glutamine amino acid molecules is necessary for this development. But there is a threshold of glutamine repeats in the huntingtin protein above which a person develops the disease. The healthy population has between 17 and 23 consecutive glutamine levels, but above 36 the symptoms of the disease develop.

The disease, considered rare, affects approximately one in 10,000 inhabitants in most European countries, although it also exists in the rest of the world in different proportions. In Spain, it is estimated that more than 4,000 people suffer from it, according to the Spanish Association of Huntington’s Korea.

A team with the participation of researchers from the Institute for Advanced Chemistry of Catalonia (IQAC), attached to the Higher Council for Scientific Research (CSIC) in Spain, has revealed the structure of huntingtin.

a new perspective

“Although the basis for the disease is not yet established, it is believed that these additional glutamine repeats cause proteins to interact with each other and facilitate the formation of protein precipitates and clumps, resulting in neuronal degeneration and symptoms such as loss of coordination and dementia”, details Ramon Crehuet, a CSIC researcher at IQAC and co-author of the study, together with Pau Bernadó and Carlos A. Elena-Real, both from the Center for Structural Biology of Montpellier in France, and other researchers. He adds: “It is known that protein with a certain number of glutamines makes it more prone to disease, but we still do not fully understand why the structure of the protein changes and becomes more toxic.”

Ramon Crehuet, IQAC researcher. (Photo: Alejandro Rodriguez)

Now, the results of this investigation reveal that there is no qualitative change between the structure of huntingtin with a pathological number of glutamine repeats, and the huntingtin of healthy people. There are only gradual changes that increase as the number of glutamines increases. “Our results provide a new perspective of the pathological threshold of the disease that goes beyond the length of the glutamine repeat chain. Knowing the structure of the protein and the mechanism of its aggregation may be the first step in designing drugs that help alleviate the symptoms and improve the lives of patients”, highlights Crehuet.

Advancing sufficiently in the knowledge of the structure of proteins can open up new possibilities for a better understanding of three-nucleotide expansion diseases, among which, in addition to Huntington’s disease, are Kennedy’s disease, myotonic dystrophy or the Fragile X Syndrome.

The new study is titled “The structure of pathogenic huntingtin exon1 defines the bases of its aggregation propensity”. And it has been published in the academic journal Nature Structural and Molecular Biology. (Source: Ana Sotres / Alda Ólafsson / IQAC / CSIC)