Autophagy vs. Huntington
Huntington's disease was proposed to be treated with autophagy
Polina Loseva, N+1
Scientists have proposed a new method to combat Huntington's disease. They found several molecules that bind simultaneously to the mutant huntingtin protein and 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. The study was published in the journal Nature (Li et al., Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds).
Huntington's disease refers to monogenic diseases, and its cause has long been known. It's all the fault of the huntingtin protein, or rather, the repeats that accumulate in its gene, at the very end. As a result, the huntingtin gene is lengthened in each generation. Patients' cells produce a protein with an abnormally long "tail" from the amino acid glutamine. Mutant proteins form aggregates that cause the death of nerve cells, therefore, like other neurodegenerative diseases, Huntington's disease is still incurable.
Zhaoyang Li from Fudan University in Shanghai, together with colleagues, began searching for substances that could cause cells to destroy the mutant protein. They suggested that autophagy, a mechanism of cellular self–eating, can be used for this purpose, during which the cell surrounds damaged proteins or even whole organelles with a membrane and splits them into monomers.
To make the cell digest huntingtin, it is necessary to deliver it to the autophagosome – a membrane bubble with digestive enzymes. Therefore, the researchers searched for substances that would simultaneously bind to the mutant protein (but not to its healthy version) and to the LC3 protein, which is part of the autophagosome membrane.
After checking 3375 substances, including both approved drugs and components of medicinal plants, the scientists identified two molecules that bind well to both proteins: 10O5 and 8F20. There were common sites in the structure of these substances, so the researchers found two more compounds of a similar structure (AN-1 and AN-2), which also bound both huntingtin and LC3.
All these molecules reduced the amount of mutant huntingtin in mouse cells by 30-40 percent. The authors of the work confirmed that the protein disappears precisely through autophagy: when this process was blocked, the effects of the substances on the cells came 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 sick mice. In addition, when the drugs were administered to 10-month-old sick mice, their symptoms of neurodegeneration became milder: in tests for holding on a rolling wheel or for grip strength, experimental animals caught up with a control group of healthy mice.
Since the amount of healthy huntingtin in the cells did not change, the researchers concluded that the substances bind specifically to the glutamine "tail" of the protein. And they suggested that this mechanism could be effective against other proteins with the same "tail". Then they tested the effect of the substances on the cells of patients with cerebrospinal ataxia of the third type, which is also characterized by the accumulation of mutant protein with excess glutamine residues, as well as on cells with green fluorescent protein, which also carried 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. Nevertheless, the authors note that their data demonstrate an important principle that can be used to find drugs for various diseases associated with the accumulation of mutant proteins.
Previously, Huntington's disease has already been tried to cope with antisense therapy: a sequence of nucleotides is injected into the body, which "sticks" to the mRNA of the mutant protein and blocks its production in the cell. So far, this method has been tested only on mice and monkeys.
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