In the architectural blueprint of our DNA, even a small repeating error can compromise the entire system. In Huntington’s disease, a specific DNA sequence expands uncontrollably, triggering progressive neurodegeneration. In a feature published in laRegione, Prof. Petr Cejka - Group Leader at the Institute for Research in Biomedicine (IRB) in Bellinzona (affiliated with USI) and Full Professor at the Universitą della Svizzera italiana - explains how his team has successfully reconstructed this expansion mechanism in vitro, paving the way for new preventive strategies to halt the disease before the onset of symptoms.
Huntington’s disease-characterised by motor and cognitive deficits alongside psychiatric disorders-stems from a repeating error. Literally. In the DNA of individuals who inherit this neurodegenerative pathology, a three-nucleotide sequence-CAG-appears, which, instead of remaining stable, tends to expand over time. "Those who have Huntington’s inherit a specific number of repeats from their parents," explains Petr Cejka , Group Leader at the Institute for Research in Biomedicine (IRB, affiliated with Universitą della Svizzera italiana) in Bellinzona and Full Professor at Universitą della Svizzera italiana. "Subsequently, during their lifetime-particularly in the brain-these repeats can undergo further expansion. When they reach a critical threshold, the disease manifests." In healthy individuals, this CAG triplet is present in the DNA in a limited and stable number of repeats; in those affected by the disease, however, the repeat count is significantly higher, representing the definitive genetic hallmark of Huntington’s.
A Turning Point
It is precisely this "jump"--the progressive expansion of the repeats-that Cejka’s laboratory has recently clarified by reconstructing the molecular mechanism under controlled conditions. "In vitro, using purified proteins, we can mix the components with the DNA to reproduce many elements of the expansion process."
This result is significant not only for basic research but also because it finally renders a mechanism that remained a mystery for decades experimentally tractable. The breakthrough arrived upon observing a crucial detail: the site and manner in which specific proteins cleave the DNA.
"The key experiment involved using a specific DNA substrate and combining the correct proteins. We observed that the proteins incise the DNA at a highly precise position: that specific site allowed us to understand how the expansion occurs."
Why did it take so long? "It was primarily a technical barrier," says Petr Cejka. "One of the fundamental protein complexes, MutL-- made of MLH1 and MLH3--was extremely difficult to isolate in the laboratory. Once we successfully expressed it, the doors to biochemical characterisation were opened." The primary molecular protagonists-MLH3, MSH3, and PMS1--were already known by the scientific community as ’genetic modifiers’ of the disease. "The novelty of our work lies in defining precisely how these factors promote genomic instability." In other words, moving beyond knowing who is involved to understanding their mode of action.
Concrete Perspectives
The inevitable follow-up question concerns therapeutics. Cejka remains cautious: "This is a long-term trajectory. Identifying the molecular aetiology does not immediately translate into a treatment. We must find a way to interfere with that mechanism: either via a small molecule or through a gene therapy approach." There is also the decisive issue of specificity. "In a patient, a drug could have off-target effects and affect other markers. Therefore, selectivity becomes fundamental." Nevertheless, this in vitro reconstruction is a step that can accelerate the next phase: the screening of inhibitory drugs. "We now have an assay that allows us to add potential inhibitors and verify if the reaction is effectively blocked." It is a simple yet powerful concept: transforming a complex biological phenomenon into a repeatable, measurable test.
What could this realistically mean for patients? The most concrete prospect is not treating the disease post-symptomatically, but rather preventing or delaying clinical onset. "If a drug or gene therapy were available, then carriers with an intermediate number of repeats-who are at risk-could be treated prophylactically to prevent the disease from manifesting."
Beyond Huntington’s
This discovery does not alter our understanding of when the disease "begins", but it reinforces the necessity of early clinical intervention. "Unfortunately, there is currently no therapy for Huntington’s," Cejka notes. "For this reason, the goal of the clinical community is to develop strategies that prevent the disease from manifesting in the first place." Furthermore, the phenomenon of genomic instability is not unique to Huntington’s. "I believe there are over fifty diseases linked to triplet repeat expansion," he explains, citing disorders such as Fragile X syndrome and Friedreich’s ataxia: distinct mutations, but shared molecular logic. This research is the product of a scientific career spanning Europe and the United States. Cejka explains that his decision to return to Switzerland was facilitated by the National Science Foundation: "It was a unique opportunity; the funding package allowed us to recruit doctoral students and commence research immediately."
His research, focused on DNA repair pathways and genomic stability, has implications extending far beyond rare diseases; the same processes underpin cancer and many other pathologies. "We require DNA repair to maintain a healthy genome," he says. "However, in cancer, certain pathways become a dependency; these pathways can then be exploited as therapeutic targets." It is a delicate balance: safeguarding DNA in healthy tissue while targeting repair mechanisms in tumour cells.
Daily challenges also include technical complexity: "Research today requires a vast array of expertise. Even with ten people in a group, one cannot delve into everything. International collaborations are essential: we work on one aspect, while colleagues overseas complement it with specialised techniques."
Beyond Research
Outside the laboratory, Cejka finds balance in nature: walking, running, and gardening. "It helps me relax and allows ideas to surface," he says. "The idea behind one of our first papers published in Nature, about ten years ago, occurred to me while running. I still remember the exact spot where it happened!" He offers young researchers a simple but concrete piece of advice: "Be curious and choose projects that you are passionate about. And find good colleagues: science is a team effort."
Content produced by the Institute for Research in Biomedicine (IRB) in Bellinzona, affiliated with USI, in collaboration with laRegione .
