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The ability to hear depends on the proteins to reach the outer membrane of the sensory cells of the inner ear. But in some types of inherited hearing loss, mutations in the protein prevent it from reaching these membranes. With the help of a zebrafish model, researchers at the Case Western Reserve University School of Medicine discovered that an antimalarial drug called artemisinin could help prevent hearing loss related to this genetic disease.
In a recent study, published in the Proceedings of the National Academy of Sciences (PNAS), the researchers found that the traditional antimalarial drug could help the sensory cells of the inner ear to recognize and transport an essential protein to specialized membranes using established pathways within the cell.
The sensory cells of the inner ear are marked by projections resembling hairs on the surface, which has earned them the nickname "hair cells". Hair cells convert sound-induced vibrations and movement into electrical signals that are transmitted through the nerves and translated into the brain as information used for hearing and balance.
The mutant form of the protein, clarin1, renders the hair cells unable to recognize them and transport them to the membranes essential for hearing using typical pathways in the cell. Instead, most mutant clarin1 proteins are trapped in the hair cells, where they are ineffective and detrimental to cell survival. Defective clarineal secretion can occur in people with Usher syndrome, a common genetic cause of hearing loss and vision loss.
The study found that artemisinin restored the function of inner ear sensory cells – and thus hearing and balance – in genetically modified zebrafish in order to dispose of human versions of an essential protein of hearing.
Lead author of the study, Kumar N. Alagramam, Ph.D., holds the Anthony J. Maniglia Chair for Research and Education, and Associate Professor in the Department of Otolaryngology of the Faculty Case Western Reserve University's medical school, has studied bringing the clarin1 mutant protein to reach cell membranes in order to improve hearing in people with Usher syndrome.
"We knew that the mutant protein generally fails to reach the cell membrane, except that patients with this mutation are born deaf," said Alagramam. "This suggested to us that at least a fraction of the mutant protein had to reach the cell membranes of the inner ear."
The Alagramam team researched all the unusual secretory pathways that mutine clarin1 could take to reach the hair cell membranes. "If we can understand how the human clarin1 mutant protein is transported to the membrane, then we can exploit that mechanism therapeutically," said Alagramam.
For the PNAS study, the Alagramam team has created several new models of zebrafish. They exchanged the zebrafish clarin1 genes with human versions – either normal clarin1 mutations or clarin1 mutations found in humans with a type of Usher syndrome, which can lead to profound hearing loss.
"Using these" humanized "fish models," said Alagramam, "we were able to study the functioning of normal clarin and, more importantly, the functional consequences of its mutant counterpart. is the first human protein involved in hearing loss was examined in this way. "
The zebrafish offers several advantages to study the audience. Their larvae are transparent, which facilitates the monitoring of the shape and function of the cells of the inner ear. Their genes are also almost identical to those of humans – especially with regard to the genes underlying the hearing. Replacing the zebrafish clarin1 with human clarin1 has created an even more accurate model.
The researchers discovered the unconventional cell secretion pathway they were looking for using fluorescent labels to track the movement of human clarin into zebrafish hair cells. Mutated clarin1 arrives at the cell membrane using proteins and trafficking mechanisms within the cell, normally reserved for misfolded proteins that are "blocked" in some cell compartments.
"As far as we know, this is the first time that a mutant human protein badociated with hearing loss is" escorted "by way of unconventional cell secretion," said Alagramam. "This mechanism could shed light on the underlying process of hearing loss badociated with other mutant membrane proteins."
The study showed that the majority of clarin1 mutants find themselves trapped in a network of tubules in the cell, like stairs and corridors helping proteins, including clarin1, to move around. one place to the other. The Alagramam team badumed that the release of the mutant protein from this tubular network would be therapeutic and tested two drugs that target it: thapsigargin (an anticancer drug) and artemisinin (a drug antimalarial).
The drugs allowed the zebrafish larvae to release the trapped proteins and to have higher levels of clarin1 in the membrane; but artemisinin was the most effective of the two. Not only did the drug help the clarin1 mutant reach the membrane, but the hearing and balance functions were better preserved in the zebrafish treated with the antimalarial drug than the untreated fish.
In zebrafish, survival depends on the normal behavior of swimming, which in turn depends on the balance and the ability to detect the movement of water, two factors related to the function of the cell ciliated. Survival rates in zebrafish expressing the clarin1 mutant jumped from 5% to 45% after artemisinin treatment.
"Our report highlights the potential of artemisinin to mitigate auditory and visual losses caused by clarin1 mutations," said Alagramam. "This could be a reusable drug, with a safe profile, to treat patients with Usher syndrome."
Alagramam added that the mechanism of unconventional secretion and activation of this mechanism with the help of artemisinin or similar drugs could also be useful for other genetic disorders involving the drug. aggregation of mutant membrane proteins in the tubular network of the cell, including sensory and non-sensory disorders.
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Gopal SR et al. "The activation of unconventional secretion pathways restores the mechanotransduction of hair cells in a USH3A model." PNAS.
For more information on the Case Western Reserve University School of Medicine, please visit: case.edu/medicine.
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