New Insights into the Structure of Huntington’s Disease Protein: Implications for Protein Aggregates in the Brain

2023-06-27 03:30:18

A team of researchers has revealed the structure of the protein responsible for Huntington’s disease. The work provides new clues to the mechanism that triggers the formation of protein aggregates in the brains of these patients.

Huntington’s disease is caused by a genetic mutation affecting the huntingtin protein. The defect is due to the expansion of the cytosine, adenine, and guanine nucleotides that code for the synthesis of glutamine in the DNA. As a result, the number of glutamines in the protein increases, which is directly related to the formation of protein aggregates in the brain.

Critical Threshold

Although the function of the huntingtin protein is unclear, it is known that it is involved in neurodevelopment and that it requires a minimum number of glutamine amino acid molecules. However, there is a threshold for the number of glutamine repeats in the huntingtin protein above which a person will develop the disease. Healthy people have between 17 and 23 consecutive glutamine levels – from 36 glutamine levels, patients show symptoms of Huntington’s disease.

A new perspective

“Although the causes of the disease have not yet been elucidated, it is believed that these extra glutamine repeats cause proteins to interact with each other and promote the formation of protein precipitates and clumps, leading to neuronal degeneration and symptoms such as loss of coordination and dementia study author Ramon Crehuet, adding: “It is known that proteins with a certain number of glutamines are more susceptible to disease, but we still don’t fully understand why the structure of the protein changes and becomes more toxic.”

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The results of the current study now show that there are no qualitative changes between the structure of huntingtin with a pathological number of glutamine repeats and huntingtin from healthy people. There are only gradual changes that increase with increasing glutamine count.

Findings for more orphans

“Our results offer a new perspective on the pathological threshold of the disease, which goes beyond the length of the glutamine chain. Knowing the structure of the protein and the mechanism of its aggregation could be the first step in developing drugs that alleviate symptoms and improve patients’ lives,” emphasizes the CSIC researcher. Studying the structure of proteins may open new avenues for a better understanding of diseases caused by the expansion of three nucleotides. In addition to Huntington’s disease, these also include Kennedy’s disease, myotonic dystrophy or fragile X syndrome.

This text is based on a press release from the Spanish National Research Council (CSIC). You can find the original publication here.

Image source: Dynamic Wang, unsplash