Botox is famous for smoothing wrinkles and treating muscle disorders, but scientists have long puzzled over how it paralyzes nerves without killing them. A new study from the Hebrew University of Jerusalem has uncovered the answer: neurons fight back. Researchers found that tiny fragments of RNA inside brain cells help block a specific kind of cell death called ferroptosis, which is triggered by stress and iron buildup. This surprising discovery explains why Botox (botulinum toxin A) causes muscle paralysis while leaving neurons alive and intact. It may also lead to more targeted and long-lasting medical uses of the toxin - and possibly new ways to treat neurodegenerative diseases.

RNA Fragments: Tiny Defenders with a Big Role

A new study led by PhD student Arik Monash, under the supervision of Professor Hermona Soreq from the Edmond and Lily Safra Center for Brain Sciences (ELSC) at the Hebrew University of Jerusalem, Professor Joseph Tam from the School of Pharmacology and Dr Osnat Rosen from the Israeli Institue of Chemical Defense, reveals how a unique class of small RNA fragments helps neurons resist the damaging effects of botulinum neurotoxin A (BoNT/A)—the world’s most potent known biological toxin.

Instead of shutting down, the neurons produce these fragments to protect themselves. The fragments work by interacting with other molecules in the cell to block ferroptosis, a form of cell death driven by oxidative stress and iron overload.

“Our findings suggest that neurons under toxic stress don't passively wait to die,” said Monash. “They actively deploy RNA fragments to push back against death signals. This response could help explain the lasting effects of botulinum-based therapeutic treatments and might one day inform therapies for other neurodegenerative conditions.”

“Our findings suggest that neurons under toxic stress don't passively wait to die. They actively deploy RNA fragments to push back against death signals.” - Arik Monash

Towards Smarter Treatments - and New Hope for Brain Diseases

The team also found that these RNA defenders share a specific genetic “signature” that helps them block harmful signals in the brain. This mechanism appears to be shared across species, including in humans and rats - suggesting it’s an evolutionarily built-in defense.

Professor Soreq, who supervised the research, explained, “We’ve known for years that botulinum toxin paralyzes muscles without destroying the neurons that control them, but we never fully understood why. This study shows that the neurons themselves mount an active, RNA-based defense, which could be harnessed to develop more precise and longer-lasting therapeutic applications.”

"This study shows that the neurons themselves mount an active, RNA-based defense, which could be harnessed to develop more precise and longer-lasting therapeutic applications." - Hermona Soreq

Read the full study: 5′LysTTT tRNA fragments support survival of botulinum-intoxicated neurons by blocking ferroptosis in Genomic Psychiatry

Researchers:
Arik Monash1,2,3, Nimrod Madrer2,4, Shani Vaknine Treidel2,4, Ofir Israeli5, Liad Hinden3, David S. Greenberg2, Joseph Tam3, Osnat Rosen6, and Hermona Soreq2,4

Institutions:
1) Department of Biotechnology, Israel Institute for Biological Research (IIBR)
2) Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem
3) Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem
4) The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem
5) Department of Biochemistry and Molecular Genetics, IIBR
6) Department of Infectious Diseases, IIBR

For a century, the Hebrew University of Jerusalem has been a beacon for visionary minds who challenge norms and shape the future. Founded by luminaries like Albert Einstein, who entrusted his intellectual legacy to the University, it is dedicated to advancing knowledge, fostering leadership, and promoting diversity. Home to over 23,000 students from 90 countries, the Hebrew University drives much of Israel’s civilian scientific research, with over 11,000 patents and groundbreaking contributions recognized by nine Nobel Prizes, two Turing Awards, and a Fields Medal. Ranked 81st globally by the Shanghai Ranking (2024), it celebrates a century of excellence in research, education, and innovation. To learn more about the University’s academic programs, research, and achievements, visit the official website at http://new.huji.ac.il/en.