HomeScience and ResearchScientific ResearchHuntington's disease offered to treat with autophagy

Huntington’s disease offered to treat with autophagy

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Scientists have proposed a new method to fight Huntington’s disease. They found several molecules that bind simultaneously to the mutant huntingtin protein and the proteins in the autophagosomes, thus directing the protein to cleavage. These substances have shown their effectiveness on cells, flies and mice, prohibiting the formation of lumps of mutant protein and reducing the symptoms of the disease.

Huntington’s disease is a monogenic disease, and its cause has long been known. Huntingtin is to blame for everything, or rather – repetitions that accumulate in its gene, at the very end. As a result, the huntingtin gene in each generation lengthens. Patients’ cells produce a protein with an abnormally long tail from the amino acid glutamine. Mutant proteins form aggregates that cause nerve cell death, so, like other neurodegenerative diseases, Huntington’s disease is still incurable.

Zhaoyang Li of Fudan University in Shanghai, along with colleagues, began searching for substances that could cause cells to destroy a mutant protein. They suggested that autophagy can be used for this purpose – the mechanism of cell self-feeding, during which the cell surrounds damaged proteins or even whole organelles with a membrane and breaks it down into monomers.

To make the cell digest huntingtin, it is necessary to deliver it to the autophagosome – a membrane vesicle with digestive enzymes. Therefore, the researchers began to search for substances that would simultaneously bind to the mutant protein (but not with its healthy version) and with the protein LC3, which is part of the autophagosome membrane.

After testing 3,375 substances, including both approved drugs and components of medicinal plants, the scientists identified two molecules that were well-connected to 10O5 and 8F20. Common areas were found in the structure of these substances, so the researchers found two more compounds of a similar structure (AN-1 and AN-2), which also linked both huntingtin and LC3.

All of these molecules reduced the amount of mutant hunting in mouse cells by 30-40 percent. The researchers confirmed that the protein disappears through autophagy: when this process was blocked, the effects of substances on the cells have come to naught. The researchers then tested that all four substances reduced the accumulation of huntingtin in drosophila neurons, and three of them (except 8F20) also in the neurons of the sick mice. In addition, when the drugs were administered to 10-month-old mice, they developed milder symptoms of neurodegeneration: in tests for holding on the rolling wheel or on grip strength experimental, animals caught up with the control group of healthy mice.

Since the amount of healthy huntingtin in cells did not change, the researchers concluded that the substances bind specifically to the glutamine “tail” of the protein. And it was suggested that this mechanism could be effective against other proteins with the same tail. Then they tested the effects of substances on the cells of patients with spinal ataxia of the third type, which is also characterized by the accumulation of mutant protein with excess glutamine residues, as well as cells with green fluorescent protein, which also contained a glutamine tail. In all these cases, the number of “tailed” proteins in the cells decreased.

The effect of the detected substances on the human body has yet to be assessed. However, the researchers note that their data demonstrate an important principle that can be used to find cures for various diseases associated with accumulation of mutant proteins.

SourceNature

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