Suppressing the Microtubule-Cutting Enzyme, Fidgetin, Allows Injured Adult Nerves to Regrow

We talk about “hard wiring” the brain but our central nervous system is a work in progress. From the first neuron through childhood and adolescence, the neuronal network grows in complexity and size but also prunes out unneeded connections using molecules like the recently characterized enzyme, fidgetin, which makes strategic cuts in the microtubule scaffolding that holds up the cell’s cytoskeleton and supports these connections. The ability of nerves to grow and prune diminishes as we mature until our adult neurons have mostly lost the power to reshape themselves.

Shown in this figure are adult rat neurons in culture
growing on a healthy substrate (dark red) toward
a substrate coated with injury-related molecules
(light red). Panel A shows fidgetin inhibition, with
the axon crossing onto the inhibitory substrate,
growing longer, and showing higher levels of
microtubules, as represented by the fluorescent green
color of the axon. Panel B shows what normally happens,
with less axon growth, no crossing onto the inhibitory
substrate, and lower levels of microtubules. Quantitative
data are shown in panels C and D.We talk about “hard wiring” the brain but our central nervous system is a work in progress. From the first neuron through childhood and adolescence, the neuronal network grows in complexity and size but also prunes out unneeded connections using molecules like the recently characterized enzyme, fidgetin, which makes strategic cuts in the microtubule scaffolding that holds up the cell’s cytoskeleton and supports these connections. The ability of nerves to grow and prune diminishes as we mature until our adult neurons have mostly lost the power to reshape themselves. This is good for the hard wiring of the nervous system but a bitter pill when adult nerves are badly injured or severed. They will not regenerate. Part of the problem is that, as we grow from an embryo to a fetus to a child to an adult, the microtubules in our nerves get more and more stable because fidgetin is hard at work cutting away the less stable microtubules. That’s one of the things that prevent regrowth. If researchers could learn to manipulate such anti-growth controls in damaged adult neurons, they might be able to coax old nerves into repairing broken connections.

Peter Baas, Lanfranco Leo, and colleagues at Drexel University have teamed with David Sharp at the Albert Einstein College of Medicine (who first identified fidgetin as a microtubule cutter) to explore the enzyme’s role in in neurons. They believe that fidgetin prevents nerves from growing out of control during development while acting as a brake on unwanted nerve growth in adults. By blocking fidgetin in the injured nerves of adult rats using a novel nanoparticle technology, Leo et al. now report that they were able to restart growth, a finding with potential implications for all kinds of nerve injury, including the most difficult challenge of allspinal cord injury. This builds on other work from David Sharp’s lab showing that inhibiting fidgetin might help the healing of wounds such as skin after burns and the heart after a coronary.

The enzyme comes by its name honestly. Fidgetin is the protein product of the fidgetin gene, which was first identified from a mutant strain of “fidget” mice, first bred in 1943 by Hans Grüneberg and named for their fidgety behavior. To block fidgetin’s actions in adult rat neurons, Leo et al. used a novel approach for making the fidgetin protein disappear. They used tiny nanoparticles, developed by Joel and Adam Friedman at Albert Einstein College of Medicine, infused with siRNA (small interfering RNA) to bind the messenger RNA transcribed from the fidgetin gene that was on its way to be translated by the cell into the microtubule-cutting fidgetin enzyme. The siRNA binding causes the mRNA to be tagged for destruction. Thus fidgetin is never translated.

“Depleting novel microtubule-related proteins represents a new and proprietary approach,” according to the researchers, who have formed a biotech company, MicroCures Inc., to commercialize their approach. Among its uses, they say, would be “tissue regeneration and repair in a wide range of therapeutic contexts including: spinal cord injury, myocardial infarction, and acute and chronic cutaneous wounds.”