Reveal the structure of the protein responsible for Huntington’s disease

A team with the participation of researchers from the Institute of Advanced Chemistry of Catalonia (IQAC) of the Superior Council for Scientific Research (CSIC) revealed the structure of the protein responsible for Huntington’s disease, a severe neurodegenerative pathology characterized by progressive disturbance of movement and cognitive function.

The results of the work, published in the journal Nature Structural and Molecular Biology, pave the way for a better understanding of the disease, as they provide new clues about the mechanism that triggers the formation of protein aggregates in the brains of these patients.

Huntington’s disease is triggered by a genetic mutation that affects the huntingtin protein. This defect is due to the expansion of the nucleotides cytosine, adenine and guanine, responsible for encoding the synthesis of glutamine in DNA, one of the 20 amino acids involved in the composition of proteins. With this, the number of glutamines in the protein increases, something that is directly related to the formation of protein aggregates in the brain.

In Spain, it is estimated that more than 4,000 people suffer from Huntington’s disease

Although the function of the huntingtin protein is unknown, so far it is known that it is involved in neurological development and that a minimal number of molecules of the amino acid glutamine are required 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 disease symptoms develop.

The disease, considered rare, affects approximately one in every 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 new perspective

“Although the basis of the disease is not yet established, it is believed that these additional glutamine repeats cause the 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 insanity. ”, details Ramon Crehuet, CSIC researcher at IQAC and one of the signatories of the work led by Pau Bernadó, from the Center de Biologie Structurale de Montpellier (France).

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The study offers a new perspective on the pathological threshold of the disease, which goes beyond the length of the glutamine repeating chain.

The Spanish scientist indicates that “it is known that the protein with a certain number of glutamines makes the appearance of the disease more prone, but we still do not fully understand why the structure of the protein changes and becomes more toxic”.

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 huntingtin from healthy people. There are only gradual changes that increase as the number of glutamines increases.

“Our results provide a new perspective on the pathological threshold of disease that goes beyond the length of the glutamine repeating chain. Knowing the structure of the protein and the mechanism of its aggregation could be the first step in designing drugs that help relieve symptoms and improve the lives of patients”, highlights the CSIC researcher.

Exploring the structure of proteins can open new possibilities for a better understanding of three diseases of nucleotide expansion, among which, in addition to Huntington’s disease, are Kennedy’s disease, myotonic dystrophy or brittle x syndrome.

REFERENCE:

Bernardo, P. et al. “The structure of pathogenic huntingtin exon1 lays the groundwork for its propensity to aggregate.” Nature Molecular and Structural Biology (2023)

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