i3S discovers a “hidden” function of DNA associated with a neurodegenerative disease
Only a small part of our DNA (about 2%) contains instructions for producing proteins. For many years, it was thought that the remaining 98% had no function and was therefore called junk DNA. Today, we know this is not true, although much of this DNA remains a mystery. A team of scientists from i3S, led by Isabel Silveira and José Bessa, has been trying to uncover its role. Recently, they discovered the function of a small region of this DNA that controls the activity of the DAB1 gene, which is essential for brain development and function.
The work, now published in the journal Cell Reports, reveals that this non-coding region of the genome acts as a regulatory element called an enhancer, controlling when the DAB1 gene is activated in nerve cells. “This gene is part of a system that helps neurons find their place in the brain and form correct connections with each other,” explains researcher Isabel Silveira.
The scientists demonstrated that, in spinocerebellar ataxia type 37 (SCA37), a rare hereditary degenerative disease, there is an abnormal appearance of a small DNA sequence that repeats multiple times [A, T, T, T, C] precisely in this enhancer. Far from being a neutral change, this mutation causes the gene to become overly active, leading to excessive production of DAB1 in neurons, with harmful effects on health.
To understand the impact of this alteration, the team used different experimental models. “In nervous system cells from patients with this ataxia, obtained in the laboratory, we observed significantly higher levels of the DAB1 gene. At the same time, in zebrafish embryos, we found that increased expression of this gene affects the growth and direction of axons, structures essential for communication between neurons,” explains Joana Loureiro, the study’s first author. These changes help explain the motor difficulties characteristic of the disease, such as loss of balance, motor coordination, and speech.
The green colour highlights the nerve bundles in the zebrafish brain, where it can be seen that overexpression of the DAB1 protein leads to a loss of nerve bundles during development.
The study also shows that this mutation acts through a particularly complex mechanism. “On the one hand, it alters how DNA controls gene activity. On the other hand, the repetitive sequence generates abnormal molecules that accumulate in cells and interfere with the normal functioning of important proteins,” adds Isabel Silveira.
In addition to the increase in DAB1, the researchers identified changes in the activity of several other genes involved in essential functions of the nervous system. “These cascading effects may help explain the overlap of symptoms between this ataxia and other neurological diseases, such as Machado-Joseph disease,” notes the i3S researcher.
Another important aspect of this work is the relevance of repetitive sequences in the human genome. “For decades, these elements were considered non-functional, but they are now believed to play important regulatory roles. When altered, as in this case, they can directly contribute to disease development,” concludes researcher José Bessa.
This study opens new perspectives for understanding genetic diseases associated with increased numbers of small DNA sequence repeats and highlights the importance of looking beyond genes themselves, exploring the regions that control their activity. In the future, this knowledge may contribute to the development of more targeted and effective therapeutic strategies.
