Μake us preferred on Google Our brain, our marvelous brain. The “conductor” of our existence has to carry out a massive number of tasks around the clock, seven days a week, from setting the rhythm of our breathing and movement to organizing our learning, memory, orientation, and emotions.
That’s why it’s made up of more than 86 billion nerve cells of different specialties, and the workload is enormous. Consider that only a very small fraction of those tens of billions of cells ever gets renewed over our lifetime; in fact, most of our nerve cells were born before we were, while we were still embryos, and they’ll leave this world along with us.
Our nerve cells are the longest-lived in the body, but that longevity comes at a cost, as it does for the body as a whole: wear and tear, the inevitable damage that builds up over time and needs repair. Our mitochondria, the cell’s energy-producing “factories,” for instance, generate harmful oxygen free radicals simply by doing their job, which they must do constantly.
How the Research Question Was Born
That introduction wasn’t incidental. It’s the backdrop to the reasoning of researchers at the Institute of Molecular Biology and Biotechnology (IMBB) at Greece’s Foundation for Research and Technology (FORTH) in Crete, who set out to answer an important question: how do nerve cells, which have to last for decades, manage to repair themselves, and what mechanism governs that repair?
The answer to this basic research question could eventually carry real practical weight, benefiting millions of people worldwide, since discovering a previously unknown mechanism for repairing nerve cells could open the door to treating cases where that mechanism has broken down, offering a route to healthy nerve function into deep old age. Fortunately, the FORTH researchers found the answer they were looking for.
The research team, postdoctoral researchers Angeliki Sotiriou and Giorgos Konstantinidis, working under the guidance of Nektarios Tavernarakis, professor at the University of Crete Medical School and research director at FORTH’s IMBB, recently published its findings, covered today by TO VIMA-Science, in the journal Nature Communications. The study was funded by the European Commission’s Horizon Europe Excellence Hubs project “CHAngeing,” along with the “Neuromitophagy” and “GliaAge” projects of the Hellenic Foundation for Research and Innovation.
Dr. Sotiriou, who devoted a significant part of her PhD to this question, explains that to discover how nerve cells manage to repair damage, the team used a widely used experimental model, the roundworm C. elegans. She notes it’s a convenient model for aging research since it has a very short lifespan, on the order of 20 to 25 days, and the organism moves from egg to adulthood in just three days. Working with C. elegans, the team uncovered the molecular mechanism behind nerve cell repair, one that also promotes longevity.
The Enzyme at the Heart of the Repair Mechanism
So what was this previously unknown mechanism, at least as far as nerve function goes? Professor Tavernarakis says at its core is an enzyme called CYLD-1.
He explains that the enzyme removes molecules of a small peptide called ubiquitin that attach to damaged proteins. Those molecules essentially act as “flags” signaling to the cell that certain proteins are broken and need to be cleared out. That clearing happens in one of two ways: either through the proteasome, which works like a document shredder for damaged proteins, sending them off to be recycled, or, when the proteasome is underperforming or insufficient, through autophagy, the process by which the cell digests its own damaged components.
The researchers found CYLD-1 plays a pivotal role in this process, which is critical for the health of the nervous system. Dr. Konstantinidis, who contributed heavily to both the original idea and the experimental and writing stages of the study, explains that the enzyme acts as the overseer of the process that clears out damaged proteins, and that its central role became clear through experiments that manipulated CYLD-1’s activity.
Specifically, when the researchers reduced the enzyme’s effectiveness through genetic manipulation, they observed increased neurodegeneration in the experimental models, similar to what’s seen in human neurodegenerative diseases.
Dr. Konstantinidis notes that in the roundworm, CYLD-1 supports cognitive abilities, memory, learning, and motor function, so reduced activity affected both mental and motor abilities. Notably, reduced CYLD-1 also shortened lifespan by roughly a third. Conversely, when the team boosted CYLD-1 activity, the animals were protected from neurodegeneration and lived longer, all without any apparent side effects.
The Same Mechanism in Humans
It’s good news that C. elegans can live longer, but how might these results matter for us? Dr. Sotiriou explains that the very same enzyme is expressed in humans and does exactly the same job there, regulating the cell’s self-cleaning process.
About six years ago, when the team began this research, existing studies had shown the enzyme is expressed at very high levels at neuronal synapses, but its mechanism of action there was unknown and unstudied until the team decided to investigate. Meanwhile, other studies have shown that patients with dementia and Alzheimer’s carry mutations in the gene that encodes CYLD, though until now that link was only a correlation, not proof. The new discovery opens the door to possible intervention targeting human CYLD.
Partnering to Develop a Drug
Since the intervention in C. elegans was genetic, using the CRISPR molecular scissors to cut genetic material at will, as well as RNA interference (RNAi), which silences genes by destroying messenger RNA or blocking its translation into protein, both approaches carry more potential risk in humans. A safer path forward would be pharmacological.
Professor Tavernarakis says the researchers have already begun down that road, partnering with a pharmaceutical company in Switzerland and clinical labs in Norway that are currently screening databases of existing drug molecules to see if any could target the CYLD enzyme.
He noted that after uncovering this important mechanism, the next step is turning the basic research into something practical, though the team is still at an early stage. He added that if a drug does eventually emerge, it would likely need to be given before symptoms of neurodegenerative diseases like Alzheimer’s appear, since once symptoms show up, the damage to neurons is usually too extensive and largely irreversible for drug treatment to be effective.
He also noted that while most neurodegenerative disease cases don’t appear to have a genetic basis, and are what’s called sporadic, some do have a genetic predisposition. For people with that kind of genetic risk, a future drug might be given preventively to head off the disease before it develops.
As the professor rightly points out, we’re still at the beginning. But the beginning, as the saying goes, is half the battle, and in this case that beginning is basic research, without which none of the achievements that improve human life would exist. That’s why basic research deserves respect, support, and above all funding to keep moving forward.
Dr. Sotiriou puts it well in closing: everyone, especially those in charge, needs to understand that without basic research there’s no progress, only the recycling of the same ideas. And in research, unlike in cells, recycling doesn’t lead to self-repair and longevity.
