Down syndrome linked to mobile DNA fragments and lamivudine

“We know that as these pieces of DNA move around, they can change gene expression,” he says. Alessandra Borgognonethe paper’s first author. Using a preclinical model of Down syndrome, the team found that certain genes associated with neurological disorders are overexpressed, contributing to the development of the pathology associated with the syndrome. The findings, published in Frontiers of Aging Neurology, show that treatment with lamivudine, an antiretroviral drug against HIV, normalizes the expression of some of these genes.

These results are consistent with previous studies that observed improvements in recognition memory, motor activity and anxiety in preclinical models following lamivudine treatment.

Retrotransposons act similarly to viruses, but without the infectious ability. These DNA fragments, like viruses, can copy themselves and insert themselves into new areas of the genome, altering gene expression.

Lamivudine is an antiretroviral drug that, in addition to preventing HIV replication, inhibits the process of ‘copy and paste’, or the movement of retrotransposons. ‘We wanted to study whether retrotransposons are indeed upregulated in Down syndrome, and see what happens if we prevent them from doing so,’ he says. Aleix Elizalde-TorrentPrincipal Investigator of the study.

Genetic abnormalities are normalized with lamivudine

The research team analyzed gene expression in brain tissue from preclinical models of Down syndrome and found that many of these mobile DNA fragments were overexpressed compared to normal mice. Similarly, numerous genes critical to neuronal function were found to be dysregulated, particularly in chromosomes 16 and 17 mice equivalent to human chromosome 21altered in Down syndrome.

“Until now, these retrotransposons have not been shown to be altered in Down syndrome, which opens up new opportunities for treatment with lamivudine,” he notes. Mara Diersena co-author of the study. In fact, the results are consistent with Diersen’s comments, as mice treated with lamivudine recovered correct expressionn some genes are altered in a mouse model of Down syndrome.

Lamivudine in other diseases

People with Down syndrome often age prematurely, and many develop characteristics similar to Down syndrome. Alzheimer’s disease from 40 years. The results indicate overexpression of genes such as Application, Ets2 and Olig2associated with the development of Alzheimer’s disease, cell death and neuronal development defects, respectively.

“This suggests that lamivudine not only has potential to treat Down syndrome, but may also slow the progression of Alzheimer’s disease and prevent aging,” he says. Bonaventure ClotetDirector of IrsiCaixa.

Although more research is needed to fully understand how retrotransposons influence gene expression in Down syndrome, these findings highlight their critical role and the promising future of lamivudine in the treatment of neurological diseases as well as aging.

The team will continue this line of work and conduct a study on people suffering from very early stages of Alzheimer’s disease. This study will be able to evaluate markers present in plasma and cells to predict and analyze the response to treatment.

Link:

Alessandra Borgognone et al. “Lamivudine modulates the expression of genes associated with neurological disorders and LINE-1 retrotransposons in brain tissue of a mouse model of Down syndrome.” Frontiers in Aging Neuroscience, 2024.

Fountain: IrsiKaisha