A research paper published in Nature Neuroscience at the beginning of October 2025 examined why TDP-43, a protein found mostly in the nucleus of cells, which is essential for normal development, especially of neurons, and for maintaining cellular/neuronal function and health, begins to malfunction and move out of place in neurodegenerative diseases. The study explored how TDP-43 misplaces itself and starts to form clumps inside the cytoplasm, which disrupts the functions of the cell and contributes to toxic protein buildup, leading to neuronal damage seen in conditions like ALS and Frontotemporal Dementia.
TDP-43 is responsible for regulating which proteins cells make, cut and edit RNA, and moves RNA to where it’s needed, repairing DNA, and self-regulates so it doesn’t make too much, but for patients who have Amyotrophic Lateral Sclerosis, or ALS, or better known to most people as Lou Gehrig’s Disease. These protein malfunctions weaken how the brain communicates and open the doors for neurodegenerative diseases.
In the case of patients with ALS, this protein builds up at abnormal rates on nerve fibers and the tiny connections where a nerve attaches to a muscle and tells it to move, called the neuromuscular junction. This junction allows signals from the brain to travel down the nerve and triggers the release of a chemical called acetylcholine, which binds to receptors on the muscle, causing the muscle to contract.
In an article on the Tel Aviv University website, the study, conducted in Prof. Eran Perlson’s lab at Tel Aviv University and led by Dr. Ariel Ionescu and Dr. Lior Ankol, with Dr. Amir Dori from Sheba Medical Center. Professor Perlson stated, “Our lab studies ALS – a fatal, incurable neurodegenerative disease. ALS affects motor neurons and causes gradual paralysis of all muscles in the body. Most patients die within 3–5 years of diagnosis, due to paralysis of the diaphragm muscles and respiratory failure. We know that in ALS, the neuromuscular junctions – where nerve fibers (axons) meet muscle cells and transmit electrical signals from the brain to the muscles — are disrupted. However, the molecular mechanisms causing this damage remained unknown until now, and consequently, no effective treatment has been developed. In this study, we wanted to get to the root of the matter and generate new knowledge that would enable the development of effective drugs for ALS.”
Researchers think muscle releases tiny RNA messages, especially one called miR-126-5p, normally keep TDP-43 levels in check, but if these signals weaken, and the amount of miR-126-5p drops, the TDP-43 may start building up in the nerves, which could disrupt local protein production, damage the neuromuscular junction, and eventually lead to motor neuron injury which is believed to be a cause of how ALS develops and progresses thoughout the body.
By mapping out the route, the full muscular and neuronal communication pathway, researchers were able to show that changing the levels of miR-126-5p directly affects how much the protein TDP-43 builds up on the nerve endings that connect to the muscle tissue itself, and may actively participate in maintaining neuronal health, suggesting that boosting miR-126-5p might be a promising therapeutic route for those with ALS.
The implications of the study imply a shift in how ALS is treated, forming new therapies to focus on the regulation of how muscle and neurons communicate with each other, boosting miR-126-5p (or other muscle-derived miRNAs) to control levels of TPD-43, and protect areas of the neuromuscular junction. It is important to note that not all ALS is the same: The models used in the research used consisted of what’s called “SOD1 — familial “or a hereditary form of ALS. Many patients have sporadic ALS or different genetic subtypes. It’s unclear whether this mechanism applies broadly. The authors acknowledge that more work is needed. ALS might begin as a breakdown in cross-cell communication long before nerves die, and fixing that communication might delay or prevent the disease.
The entire research can be read here
Update: VectorY Therapeutics, a biopharmaceutical company, has been cleared by the FDA to proceed with its PIONEER-ALS Phase I/II clinical trial of VTx-002, an antibody that targets toxic forms of TDP–43 protein. Preclinical studies showed that VTx-002 reduced harmful TDP-43 aggregates and restored normal RNA processing, and impro
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