Unlike the brain and spinal cord, peripheral nerve cells, whose long extensions reach the skin and internal organs, are capable of regenerating after injury. This is why injuries to the central nervous system are considered irreversible, while damage to peripheral nerves can, in some cases, heal, even if it takes months or years. Despite decades of research, the mechanisms behind peripheral nerve regeneration remain only partially understood. In a new study published in Cell, researchers from Prof. Michael (Mike) Fainzilber’s lab at the Weizmann Institute of Science discovered that a family of hundreds of RNA molecules with no known physiological function is essential to nerve regeneration. Remarkably, the study showed that these molecules can stimulate growth not only in the peripheral nervous system of mice but also in their central nervous system. These findings could pave the way for new treatments for a variety of nerve injuries and neurodegenerative diseases.
For a peripheral nerve to regenerate, it must maintain communication between the neuron’s cell body and its long extension – the axon – which in humans can reach more than a meter in length. In a series of studies over the past two decades, Fainzilber’s lab has revealed key components of this communication: proteins that act like postal couriers, delivering instructions for the production of growth-controlling factors and other proteins, from the cell body to the axon. These molecular couriers also help assess the distance between the cell body and the axon tip, allowing the neuron to modulate its growth accordingly. Yet one central issue remained: What triggers the regenerative growth after injury, and why does this not happen in central nervous system cells?
“”While the growth acceleration observed in our study is not yet sufficient to address clinical paralysis, it is definitely significant”
In the new study, Dr. Indrek Koppel of Fainzilber’s lab, in collaboration with Dr. Riki Kawaguchi of the University of California, Los Angeles (UCLA), examined a specific kind of gene expression in the peripheral nerves of mice following injury. The researchers were surprised to find that one day after damage, the neurons increased the expression of an entire family of short genetic sequences called B2-SINEs, whose role was previously unknown. These sequences do not encode any proteins, and because they are known for “jumping” around the genome, meaning that they can appear at the wrong place or time, they have a bad reputation. But the researchers found that after injury, the neurons began expressing many B2-SINE RNA transcripts, in parallel with other processes preparing the cell for regeneration and repair.
However, B2-SINE is an enormous family, comprising some 150,000 sequences scattered throughout the mouse genome. The initial analysis could not determine which of these were responsible for promoting growth. Dr. Eitan Erez Zahavi, also of Fainzilber’s lab, who led the new study alongside Koppel, used bioinformatics tools to identify 453 B2-SINE sequences that are highly expressed after injury, promoting nerve growth. Collaborating with international research teams, the scientists showed that this overexpression after injury is unique to peripheral nerve cells and does not occur in the central nervous system.
The periphery leads, the center follows
The researchers then tested whether B2-SINEs from peripheral nerve cells could also stimulate neuronal growth in the central nervous system. They induced retinal neurons in mice to overexpress RNA molecules of the B2-SINE type and observed faster regeneration after injury. A similar experiment in the mouse motor cortex – the brain region that controls muscle movement via long axons projecting to the spinal cord – showed that neurons expressing high levels of B2-SINE also regenerated faster than control neurons.
“There are still no effective treatments to accelerate nerve cell growth and regeneration,” Fainzilber notes. “While the growth acceleration observed in our study is not yet sufficient to address clinical paralysis, it is definitely significant. Of course, the path from basic research to clinical application is long, and we must make sure that enhancing growth mechanisms does not, for example, increase the risk of cancer.”
One final mystery remained: How do B2-SINE RNA molecules actually promote regeneration? With help from Prof. Alma L. Burlingame’s group at the University of California, San Francisco, the researchers discovered that these RNAs promote a physical link between the molecular “couriers” carrying instructions for producing growth-associated proteins and the ribosomes that read these instructions and carry them out. This means that production of the critical factors takes place closer to the cell body rather than to the tip of the axon. The researchers believe that this signals to the neuron that it is “too small,” triggering a growth response.
“There are over a million sequences called Alu elements in the human genome, the human equivalent of B2-SINEs in mice,” says Fainzilber. “These molecules had been previously shown to bind to ribosomes and mail couriers, but why this happens was unknown. We’re now trying to determine whether Alu or other noncoding RNA elements are involved in nerve regeneration in humans.”
“Recovery from peripheral nerve injuries, or from systemic diseases like diabetes that affect these nerves, can be very slow,” he adds. “That’s why we’re now testing a therapy that might speed up regeneration by mimicking B2-SINE activity. This therapy involves small molecules that connect the couriers to ribosomes while keeping them close to the nerve cell body, promoting faster growth. We are conducting this research in collaboration with Weizmann’s Bina unit for early-stage research with applicative potential.”
Beyond promoting peripheral nerve regeneration, the new study also hints at an even broader prospect: regeneration in the central nervous system. “We are currently working with UCLA on a study showing that the mechanism we discovered plays a role in recovery from stroke in mouse models,” Fainzilber says. “Additionally, we’re collaborating with Tel Aviv University, Hebrew University and Sheba Medical Center to study its possible role in ALS, a progressive neurodegenerative disease. Neurodegenerative conditions affect many millions of people worldwide. While the road ahead is long, I truly hope we’ll one day be able to harness our newly discovered regeneration mechanism to treat them.”