At Aarhus University in Denmark, scientists have pinpointed the very switch that tells our cells when to start clearing out their trash. This discovery not only reveals how the body tidies up after itself but also hints at new ways to fight devastating disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.
Many serious diseases arise because cells fail to dispose of waste that accumulates because of mutations, ageing or other causes. Cells handle the clean-up with autophagy – literally “self-eating”. Think of it as one of the body’s main cleaning and recycling services; the cell wraps what needs to go in a bag and sends it to its own acid bath, the lysosome, where everything is broken down and reused. Scientists still do not know exactly how autophagy works.
A series of new studies in Denmark has shed light on important aspects of this cell cleaning system. Writing in Nature Structural & Molecular Biology, Fulvio Reggiori and his team at Aarhus University show that a tiny membrane that will ultimately form the trash bag only starts to grow once it links up with the cell’s own factory of lipids, the building blocks used to generate the waste bag. Once the link is made, a protein called Ypt1 works like a switch, flicking on the whole clean-up system.
“We can now show that the large waste bag only grows when the machinery delivers the building blocks, in this case lipids,” explains Fulvio Reggiori, Professor at the Department of Biomedicine, Aarhus University.
The garbage bag that comes alive
He compares the process to a garbage bag that hangs limp until it sits properly in the bin. Only then can it hold waste. Inside the cell, the same principle applies: the initial membrane grows when it connects with the lipid factory, and Ypt1 gives the green light, signalling that everything is ready.
To demonstrate this link, the researchers combined genetic manipulations with advanced fluorescence microscopy. They attached glowing tags to the first tiny membrane and watched: it only expanded when it touched the cell’s lipid factory. Under the microscope, the tags lit up as little dots, revealing where the membrane was – and whether it was properly connected.
When they turned off the genes behind Ypt1, the clean-up stalled. Switching them back on – and following the glowing dots – enabled the team to slowly trace how the system works. These findings about how the machinery starts up also highlight why it matters: when the system slows down or breaks down entirely, waste begins to accumulate, with serious consequences for health.
When the garbage truck never shows up
Autophagy is one of the cell’s main clean-up systems. It clears out worn-out parts and recycles the useful pieces. When the process runs, the cell stays healthy. When it fails, waste piles up, like in a household where the garbage truck never arrives. Autophagy weakens with age, and this is thought to be one of the causes of ageing, because cells become less efficient at cleaning up damage and this damage then accumulates.
This is exactly the problem in Alzheimer’s disease, in which proteins form harmful clumps: tau and beta-amyloid. Tau accumulates inside neurons, and beta-amyloid builds up outside and disrupts communication between cells. In amyotrophic lateral sclerosis, the TDP-43 protein forms clumps in the nerve cells that control muscles. In Parkinson’s disease, alpha-synuclein piles up in neurons and destroys their function. The same trend is seen in other nervous system diseases and in certain pathologies affecting other organs.
Fulvio Reggiori emphasises that health suffers every time the waste system fails or does not recognise what needs to be removed. This is why, he notes, its detailed understanding is so critical. Only then is there a chance to fix the system or activate it to remove the harmful clumps. He also stresses that the balance is fragile: the machinery can protect or can harm, and any therapy must fine‑tune the process rather than simply switch it on or off.
The grinder that shreds deadly clumps
From this concern about balance, the story turns to new findings about clumps. In Nature Cell Biology, Fulvio Reggiori’s group reported that cells handle very large protein accumulations in a special way. Their study showed that a giant clump cannot disappear in one piece. It must first be fragmented before the autophagy waste bag can take it in. Inside the cell, special machinery fragments the clumps into smaller pieces so that the waste system can collect them and send them for degradation. When the researchers switched off the genes encoding the fragmentation proteins, the clumps remained as immovable blocks. When the fragmentation machinery worked, the clean-up could continue.
Fulvio Reggiori explains that the fragmentation machinery offers a new way of understanding how cells get rid of clumps that would otherwise be impossible to move. This, he adds, opens a path to treating diseases when such clumps drive cell death.
“If we can help the cell to both fragment the clumps and form the waste bags, then a combination treatment could become a more effective way forward,” says Fulvio Reggiori.
When influenza sneaks in with the cleaners
Some of the things that keep the autophagy waste system running have roles in other cellular processes. In a third article, published in Science Advances, the researchers show how influenza virus exploits one of the waste system components to enter the cell. The process works like a transport system that assembles the centre for cell division. The virus hitches a ride and uses the force to burst its own membrane and release its genetic material, which then takes control of the cell from within.
“The waste system is not just a clean-up crew and is woven into many other biological processes,” Fulvio Reggiori points out. “That makes understanding the details all the more important before we try to manipulate it.”
From Nobel Prize to next-generation medicine
Autophagy was first described in the 1960s, but for decades researchers had only sporadic insight into the process. In the 1990s, Japanese scientist Yoshinori Ohsumi succeeded in mapping the first genes that govern autophagy. The work earned him the Nobel Prize in 2016. Since then, the field has exploded, and autophagy is now one of the most dynamic areas in biomedical research.
The Aarhus team’s findings add fresh pieces to the puzzle. Yoshinori Ohsumi and other pioneers laid the foundation, and Fulvio Reggiori’s group as well as other researchers around the world are now revealing how the system fine-tunes itself and how it spots what needs to be removed. This knowledge may eventually be translated into new treatments.
The discoveries are highly significant for neurodegenerative diseases, but their reach is broader. Several types of cancer exploit the autophagy waste system to promote their own survival, and infections from bacteria to viruses can also affect it. Pharmaceutical companies are actively searching for compounds that can turn autophagy up or down. So far, results have been mixed. There are promising inhibitors, but specific activators that can boost the cell’s capacity to degrade unwanted waste are still missing.
Only at the beginning
Fulvio Reggiori emphasises that “we are still only at the beginning”. Many pieces are in place, and his group has contributed some of them, but many are still missing. He points to the big unanswered questions: how fragmentation is controlled, why it sometimes fails, and how the system might be targeted for treatments. The more these mechanisms are understood, the closer researchers get to treatments that can keep cells healthy even when disease threatens.
He also highlights the importance of the research setting in Aarhus, with its solid infrastructure and cross‑disciplinary environment.
“By combining biochemistry, cell biology and imaging technologies such as advanced fluorescence and electron microscopy, we can spot details that none of the techniques would reveal on their own,” he concludes.
