Down syndrome linked to mobile DNA fragments, which could be stopped with lamivudine

Our genome contains DNA fragments called retrotransposons, which can move around the genome and alter gene expression. Now, a study conducted by IrsiCaixa —a centre jointly supported by the "la Caixa" Foundation and the Department of Health of the Generalitat de Catalunya— and the Centre for Genomic Regulation (CRG) demonstrates for the first time that these retrotransposons are abnormally expressed in Down syndrome. "We know that these DNA fragments can alter gene expression when they move," says Alessandra Borgognone, senior researcher at IrsiCaixa. The team has identified, in a mouse model of Down syndrome, that some genes related to neurological deterioration are overexpressed, contributing to the pathology associated with this syndrome. The results, published in Frontiers in Aging Neuroscience, show that administering lamivudine, an antiretroviral against HIV, normalizes the expression of some of these genes. These findings align with previous studies where an improvement in cognitive ability was observed in preclinical models following treatment with lamivudine.

Retrotransposons act similarly to viruses, but without infective capacity. These DNA fragments, like viruses, can copy themselves and insert into new genome regions, altering gene expression. Lamivudine is an antiretroviral that, besides preventing HIV replication, inhibits this "copy and paste" process, i.e., the movement of retrotransposons. "We wanted to demonstrate if there was really an increase in retrotransposon activity in Down syndrome and see what happened if we prevented their activity," says Aleix Elizalde-Torrent, senior researcher at IrsiCaixa.

Retrotransposons and deregulated genes that could be normalized with lamivudine

The research team analyzed gene expression in brain tissues of preclinical Down syndrome models and found that many of these mobile DNA fragments are overexpressed compared to normal mice. They also identified a dysregulation of numerous genes crucial for neuronal function, especially on mouse chromosomes 16 and 17, equivalent to human chromosome 21, altered in Down syndrome. "Until now, it had not been shown that these retrotransposons were altered in Down syndrome, opening new treatment possibilities with lamivudine," notes Mara Dierssen. The results indeed align with Dierssen's comments, as mice that received lamivudine recovered the correct expression of some altered genes in the Down syndrome mouse model.

Extending the potential of lamivudine to other diseases

People with Down syndrome tend to age prematurely, and many develop Alzheimer's-like characteristics from age 40. The results indicate an overexpression of genes like App, Ets2, and Olig2, related to Alzheimer's development, cell death, and neuronal development defects, respectively. "This suggests that lamivudine not only has potential in treating Down syndrome but could also slow Alzheimer's progression and prevent aging," asserts Bonaventura Clotet, director of IrsiCaixa. While more research is needed to fully understand how retrotransposons affect gene expression in Down syndrome, these results highlight their crucial role and the promising future of lamivudine in treating neurological diseases and aging. The team is currently continuing the study of lamivudine in Alzheimer's patients in collaboration with the Pasqual Maragall Foundation.