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When the body needs to repair nerve injury, the machinery is already in place. Hidden within nerve cells is a “one-ring-to-rule-them-all” kind of trigger: a molecular machine that can ramp up the synthesis of the necessary proteins on demand, right at the injured spot. As reported in Science, Weizmann Institute of Science researchers, together with collaborators, have now revealed how this nerve-repair mechanism is regulated. The findings shed new light on key elements of cellular growth and repair, opening up new directions for the future development of innovative treatments for a wide variety of disorders.
The team of Prof. Mike Fainzilber in Weizmann’s Biomolecular Sciences Department wanted to know how nerve repair is aided by a protein called mTOR, which serves as a central regulator of protein synthesis in general and of neuronal growth in particular. They discovered that this protein resembles J. R. R. Tolkien’s “one ring to rule them all,” not only for its crucial function but also because it turned out that, like Tolkien’s “one ring,” mTOR can be hidden from view.
In a study in mice, Dr. Marco Terenzio and other members of Fainzilber’s team found that mTOR molecules appeared at the site of injury in the sciatic nerve. What surprised the scientists was the speed with which mTOR turned up. The sciatic nerve is extremely long; it is made up of neurons whose cell bodies reside in the lower back, but their extensions − called axons − run along the leg all the way down to the foot. Had mTOR been produced in the cell body, it would have taken half a day to reach an injured spot in the mid-thigh, yet the scientists detected a sharp rise in mTOR levels within two to three hours. They concluded that the protein must have been manufactured on the spot.
Using an advanced version of mass spectrometry that makes it possible to identify new proteins in living tissue as they are being made, the scientists – working with colleagues in the laboratory of Prof. Alma Burlingame of the University of California, San Francisco – determined that in the wake of nerve injury, mTOR stimulates its own production. Increased levels of mTOR then trigger the localized synthesis of other proteins that are essential for the survival and repair of the nerve. When the scientists blocked the production of mTOR after injury, no rise in the synthesis of other proteins occurred in the injured axon.
But how does the increase in the production of mTOR come about? Together with the laboratory of Prof. Jeffery Twiss of the University of South Carolina, the researchers found that even in the absence of injury, instructions for making mTOR are present throughout the axon in the form of messenger RNA, or mRNA molecules, which contain the genetic “blueprint” for making protein. These mRNAs are continuously transported to various parts of the axon, replenishing their supply. When an injury occurs, they are right there, ready to produce the mTOR needed for repair. To test how this mechanism works, the scientists used gene editing to remove a segment of the mRNA molecule that enables its transport: they then saw that, indeed, no protein synthesis took place and the injured axon failed to survive.
Explains Fainzilber: “Just as Tolkien’s ‘one ring to rule them all’ can wreak havoc in the wrong hands, so can mTOR be dangerous if activated at the wrong time or place within the cell. It could cause unregulated nerve growth leading to pain, or excessive cellular growth resulting in cancer. Thus manufacturing mTOR only when and where it’s needed, based on locally available mRNA instructions, is a much safer and faster way of providing a controlled supply of this master switch.”
In the wake of nerve injury, mTOR stimulates its own production
The same latent mechanism is probably responsible for manufacturing mTOR in situations that are unrelated to nerve injury. It could, for instance, help produce the mTOR needed for the nerve growth that occurs in the human body as it continues to develop in the first two decades of life, or in a variety of other cellular processes in which mTOR plays a pivotal role.
Defects in mTOR functioning have long been shown to be involved in a wide range of diseases, including cancer, diabetes and obesity. Drugs that interfere with mTOR’s activity already exist on the market. The hidden mechanism for the manufacture of mTOR revealed in the Weizmann study could help develop new approaches to regulating mTOR activity in injury and disease.
The research team also included Dr. Sandip Koley, Nitzan Samra, Dr. Ida Rishal, Dr. Letizia Marvaldi, Agostina Di Pizio, Ella Doron-Mandel, Dr. Rotem Ben Tov Perry and Dr. Indrek Koppel of Weizmann’s Biomolecular Sciences Department; Dr. Qian Zhao, Dr. Anatoly Urisman, Dr. Juan A. Oses-Prieto and Dr. Craig Forester from Prof. Burlingame’s lab at the University of California, San Francisco; and Dr. Pabitra K. Sahoo, Dr. Cynthia Gomez and Dr. Ashley L. Kalinski from Prof. Twiss’s lab at the University of South Carolina.
Prof. Michael Fainzilber's research is supported by the Laraine and Alan A. Fischer Laboratory for Biological Mass Spectometry; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Zuckerman STEM Leadership Program; the Rising Tide Foundation; the estate of Florence and Charles Cuevas; the estate of Lilly Fulop; the European Research Council; the Minerva Foundation; and the Israel Science Foundation. Prof. Fainzilber is the incumbent of the Chaya Professorial Chair in Molecular Neuroscience.
Dr. Terenzio was partly supported by a Senior Koshland Postdoctoral Award.