Gentamicin against dementia
Common dementia was offered to be treated with an antibiotic
Polina Loseva, N+1
The antibiotic gentamicin was suggested to be used as a possible medicine against temporal-frontal dementia. It turned out that it is effective in one of the mutations that causes this disease: it forces the cell to ignore the mutation and assemble a full-sized protein. In the future, it remains to be seen whether this method helps to cope with the symptoms of the disease. The study was published in the journal Human Molecular Genetics (Kuang et al., Frontotemporal dementia nonsense mutation of progranulin rescued by aminoglycosides).
Temporal-frontal dementia is the second most common type of dementia after that caused by Alzheimer's disease. In about half of cases, it is transmitted in generations, and every fifth case of inheritance is associated with a mutation in the progranulin gene.
The biological functions of the progranulin protein are still not clear, however, judging by the fact that it is found in membrane organelles – lysosomes, Golgi apparatus and endosomes – it is somehow connected with the absorption and release of substances by the cell. In familial dementia, the progranulin gene carries a point mutation, as a result of which a stop codon appears in its middle - a signal of the end of protein construction. In this case, the cell builds a truncated version of the progranulin, which does not perform its functions.
Lisha Kuang together with colleagues from The University of Kentucky proposed to use aminoglycoside antibiotics for the treatment of temporal-frontal dementia (these include, for example, gentamicin). They are known for suppressing protein synthesis in bacteria, and in eukaryotes they force the ribosome to "jump over" the stop codon and continue to build a protein chain. Therefore, scientists have suggested that antibiotics will allow nerve cells to "close their eyes" to the mutation and synthesize a full-sized progranulin. There are already examples of such therapy in the world that has passed clinical trials – this is the drug ataluren, which has already been approved in Europe for the treatment of Duchenne myodystrophy, another disease caused by a mutation.
The researchers tested their assumption on mouse neuroblastoma cells. They were injected with a plasmid with a wild-type progranulin gene or with a mutant gene, and then acted with different aminoglycosides. Of the 11 common antibiotics of this type, only gentamicin and the drug G418 were effective: in their presence, the cells produced a full-fledged progranulin.
However, both drugs affected only one of the three possible types of mutation that the scientists worked with. Therefore, they then set up a series of experiments to make sure that the effect of antibiotics is not an artifact. They tested different concentrations of drugs and different exposure times and found that antibiotics have a dose-dependent effect: the higher their concentration and the longer they stay in the cell, the more progranulin it produces.
Then the researchers checked that the resulting protein retains its functions. The fact is that when the ribosome "skips" the stop codon, it embeds a random amino acid in the middle of the protein, and this may be enough to disrupt the protein structure. However, in cases where antibiotics worked and the cells synthesized progranulin, it was then possible to detect it in the same areas of the cell as usual. Since it is still unknown exactly what functions it performs, the authors of the work considered this argument sufficient to conclude that the protein turned out to be viable.
Thus, scientists have confirmed that an antibiotic can help to cope with the consequences of a point mutation. It is too early to talk about the effectiveness of this method in real patients, in this work, the researchers simply showed that such therapy is possible. If it is possible to work it out on animals, and then on humans, then this will be the first drug against dementia, even though it can only be effective with a specific mutation.
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