Israeli researchers identify potential new target for neurodegenerative disease treatments
Baku, November 3, AZERTAC
Israeli researchers have identified a cellular process that influences how cells protect themselves against damaged proteins, uncovering a potential new avenue for studying neurodegenerative diseases such as Alzheimer’s and Huntington’s, according to TPS-IL.
The findings could point to a different approach to combating these diseases: rather than targeting harmful proteins directly, researchers may eventually be able to strengthen the cell’s natural defenses against protein buildup. The discovery could also help explain why these defenses weaken with age, making the brain more vulnerable to neurodegenerative diseases.
Alzheimer’s disease is a progressive brain disorder and the most common cause of dementia, impairing memory, thinking and everyday functioning. Huntington’s disease is an inherited neurological disorder that causes the progressive breakdown of nerve cells, leading to involuntary movements, cognitive decline and psychiatric symptoms. Both are associated with abnormal protein accumulation in the brain.
In experiments involving microscopic worms, researchers found that reducing the activity of a process called UFMylation strengthened several natural defenses against damaged and misfolded proteins, helping the animals withstand harmful proteins associated with both diseases.
UFMylation is a process in which cells attach a small protein called UFM1 to other proteins, changing how they function. Although it plays an important role in normal cell activity, its broader effects on aging and protein quality control have remained unclear.
The intervention reduced paralysis in an Alzheimer’s disease model, improved movement in a Huntington’s disease model and extended the worms’ lifespans by approximately 13 percent.
The findings, published in the peer-reviewed journal Nature Communications, offer new insight into how aging affects the cellular systems responsible for keeping proteins healthy.
The study was led by Prof. Ehud Cohen of the Institute for Medical Research Israel-Canada at the Hebrew University of Jerusalem’s Faculty of Medicine, in collaboration with researchers from the National Institute of Biological Sciences in Beijing, China.
Proteins perform essential functions throughout the body but must maintain the correct shape to work properly. Cells rely on quality-control systems to ensure proteins fold correctly and that damaged or misfolded proteins are repaired or removed. These systems become less efficient with age, allowing abnormal proteins to accumulate and form harmful clumps.
Testing the Cellular Defenses
To investigate UFMylation’s role, the researchers used *Caenorhabditis elegans*, a microscopic worm commonly used in aging research. They studied worms engineered to produce amyloid-beta, a protein associated with Alzheimer’s, and others producing abnormal proteins resembling those involved in Huntington’s disease. These models allow scientists to study disease-related cellular processes, although the worms do not develop the human conditions themselves.
Reducing UFMylation made the worms more resistant to both types of harmful proteins. In the Alzheimer’s model, paralysis, used to measure the proteins’ toxic effects, was approximately 35 percent lower by the 12th day of adulthood than in untreated worms of the same strain.
The intervention also improved movement in worms carrying Huntington’s-like proteins, including in experiments involving proteins produced in nerve cells. Among worms carrying toxic proteins, reducing UFMylation extended lifespan by approximately 13 percent compared with untreated animals.
Further experiments showed that reducing UFMylation improved the quality control of newly produced proteins, reduced harmful protein clumps and increased the breakdown and removal of damaged proteins.
This suggests that UFMylation regulates several parts of the cellular machinery responsible for maintaining healthy proteins, rather than affecting only one disease-related protein.
“As we age, our cells become less effective at dealing with damaged and misfolded proteins, and this is closely connected to diseases such as Alzheimer’s and Huntington’s,” Cohen said. “What we found is that changing the activity of UFMylation can strengthen the cell’s ability to cope with these harmful proteins.”
The researchers also identified 155 proteins affected by UFMylation, including several involved in aging and maintaining healthy protein networks. Some became more heavily modified as the worms aged, while others became less so, suggesting that the process changes over an organism’s lifetime.
However, experiments with human cells revealed an important complication: completely eliminating UFMylation impaired their ability to manage damaged proteins. Any potential treatment would therefore need to adjust the process carefully rather than block it altogether.
“We are still far from translating this into a treatment,” Cohen said, adding that the findings could help explain why diseases associated with abnormal protein accumulation become more common later in life.
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