Scientists Discover Game Changing Method to Fix Protein Misplacement in Cells, Offering Hope for Neurodegenerative Diseases
Nikhil Prasad Fact checked by:Thailand Medical News Team Apr 15, 2025 20 hours, 31 minutes ago
Medical News: In an exciting new development, researchers from Illinois State University, USA, have introduced a pioneering approach that could reshape how we treat a range of neurodegenerative disorders, such as Alzheimer’s, Parkinson’s disease, and ALS. The team has developed a unique tool called targeted relocalization activating molecules, or TRAMs, which can help redirect misplaced proteins inside cells to where they are supposed to be.
Small molecules can elicit the targeted relocalization of proteins. Bifunctional small molecules have been developed to bind to a protein called FKBP12F36V at one end and an endogenous or engineered shuttle protein in the cytoplasm or the nucleus at the other end. When FKBP12F36V is fused to a target protein, the small molecules bind to the shuttle and the FKBP12F36V-tagged target protein simultaneously. The shuttle proteins subsequently transport the target protein between cellular compartments, for instance, from the cytoplasm into the nucleus. This method can be exploited to induce the targeted relocation of misplaced proteins inside mammalian cells.
Proteins are the workhorses of the human body. But for them to do their jobs properly, they need to be in the right place at the right time. When proteins are mislocated—due to genetic mutations, stress, or aging—they can accumulate in the wrong parts of cells and cause serious damage. This mislocalization is a well-known feature in many diseases. This
Medical News report explores how TRAMs, small molecules developed by the research team, can help solve this long-standing problem.
The researchers—Grace Hohman, Ava Watson, and Dr. Mohamed A. Eldeeb, all from the Department of Chemistry at Illinois State University—demonstrated how TRAMs work through a series of detailed cell-based experiments. These molecules are designed to attach to two different proteins: a mislocated protein and a special helper protein called a shuttle. The shuttle acts like a taxi service, guiding the wayward protein back to its correct location inside the cell. The team showed that this method is not only effective but also does not destroy the proteins, unlike some existing treatments which eliminate the proteins entirely.
How TRAMs Work and Why They Matter
The TRAMs act like molecular matchmakers. One part of the molecule binds to the misplaced protein, and the other binds to the shuttle protein, which contains strong signals that help it move to specific areas within the cell. Depending on what needs to be fixed, the shuttle can be programmed to drag the protein from the nucleus to the cytoplasm, or vice versa.
In one of their key experiments, the team focused on a nuclear protein called NMNAT1 and used a shuttle with a nuclear export sequence to pull it into the cytoplasm. The process worked efficiently and in a dose-dependent manner across four different cell lines. They further proved the approach could work in the opposite direction by using estrogen and glucocorticoid receptors to draw proteins into the nucleus. These demonstrations revealed the powerful
versatility of TRAMs.
Importantly, they found that different shuttle proteins had different strengths and that choosing the right shuttle was critical for achieving efficient relocalization. They even developed a localization scoring system to evaluate and compare the effectiveness of different shuttles.
Targeting Mutant Proteins Linked to ALS and Alzheimer’s
Taking their study a step further, the researchers explored how TRAMs could work on disease-related proteins. They tested three known mutant proteins associated with neurodegenerative conditions and successfully relocated all of them using TRAMs. One standout case was a mutated version of the FUS protein, commonly found in patients with ALS. This mutant form tends to clump into toxic granules in the cytoplasm of neurons. Using TRAMs, the researchers were able to move the protein back into the nucleus, leading to a significant reduction in granule formation.
This discovery suggests that TRAMs might not only prevent toxic clumps from forming but could potentially reverse some of the damage already done in diseases like ALS.
Protecting Neurons with Relocated Proteins
Another stunning finding came from experiments using neurons. The researchers looked at a protective protein from mice called mNMNAT1. When this protein is sent to nerve endings (axons), it helps prevent degeneration after nerve injury. By using TRAMs to move mNMNAT1 into the axons of nerve cells, the scientists were able to significantly extend the lifespan of these cells, even after damaging them. Control neurons died within 48 hours, while the treated ones remained healthy for up to 96 hours.
This not only proves that TRAMs can move proteins, but that relocated proteins can remain functional—or even gain new protective functions in their new locations.
The Future of Protein Relocalization Therapy
The implications of this discovery are enormous. Rather than destroying harmful proteins, we may now have the option to fix them simply by putting them in the right place. The researchers acknowledge some limitations, such as the challenge of applying this in live animal models or humans, and the need for further testing. However, this work lays a strong foundation for future therapies that may one day treat complex diseases by correcting protein misplacement.
In conclusion, the TRAM system represents a revolutionary shift in cellular biology and therapeutic design. It offers a safer, more targeted alternative to existing treatments that rely on protein degradation. By restoring protein placement rather than eliminating them, TRAMs preserve essential cellular functions while eliminating the toxic consequences of mislocalization. If future studies confirm their effectiveness in live organisms, TRAMs could become a transformative tool in the treatment of neurodegenerative diseases—and possibly cancer and other conditions linked to protein errors.
The study findings were published in the peer-reviewed journal: Biology.
https://www.mdpi.com/2079-7737/14/4/420
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