How to Protect Neurons and Encourage Their Growth

Many neurodegenerative conditions, from glaucoma to Alzheimer’s disease, are characterized by injury to axons — the long, slender projections that conduct electrical impulses from one nerve cell to another, facilitating cellular communications. Injury to axons often leads to neuronal impairment and cell death.

Researchers know that inhibiting an enzyme called dual leucine zipper kinase (DLK) appears to robustly protect neurons in a wide range of neurodegenerative diseases models, but DLK also inhibits axonal regeneration. Until now, there have been no effective methods to modify genes to improve both the long-term survival of neurons and promote regeneration.

In a paper published December 14, 2020 in PNAS, a multi-university team led by researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health identified another family of enzymes called germinal cell kinase four kinases (GCK-IV kinases) whose inhibition is robustly neuroprotective, while also permitting axon regeneration, making it an attractive therapeutic approach for treating at some neurodegenerative diseases.

Example of retinal ganglion cells with axons and dendrites in the retina of a healthy eye.

We basically figured out that there are a set of genes that, when inhibited, allow optic nerve cells to survive and regenerate,” said senior author Derek Welsbie, MD, PhD, associate professor of ophthalmology in the Viterbi Family Department of Ophthalmology at Shiley Eye Institute.

Prior to this work, the field knew how to get these cells to survive, but not regenerate. Conversely, there are ways to promote regeneration, but then the survival was rather modest. Of course, for a successful strategy of vision restoration, you need both and this is a step in that direction.”

Source: https://ucsdnews.ucsd.edu/

How To Regenerate Optic Nerve Cells

Scientists have found a new way to regenerate damaged optic nerve cells taken from mice and grown in a dish. This exciting development could lead to potential eye disease treatments in the future. Damage to full-grown nerve cells causes irreversible and life-altering consequences, because once nerve fibres mature, they lose their ability to regenerate after injury or disease. The new experiments show how activating part of a nerve cell’s regenerative machinery, a protein known as protrudin, could stimulate nerves in the eye to regrow after injury.

With more research, the achievement is a step towards future treatments for glaucoma, a group of eye diseases which cause vision loss by damaging the optic nerve (that links the eye to the brain).

What we’ve seen is the strongest regeneration of any technique we’ve used before,said ophthalmologist Keith Martin from the University of Melbourne in Australia. “In the past it seemed impossible we would be able to regenerate the optic nerve but this research shows the potential of gene therapy to do this.”

In this study, scientists stimulated nerve cells of the eye to produce more protrudin, to see if this would help protect the cells from damage and even repair after injury. First, in optical nerve cells cultured in a dish, the researchers showed that ramping up protrudin production stimulated regeneration of nerve cells that had been cut by a laser. Their spindly axons regenerated over longer distances, and in less time, than untreated cells.  Next, adult mice were administered gene therapy – an injection straight into the eye – carrying instructions for nerve cells to bump up protrudin production. As painful as that sounds, this procedure can actually be done safely in people (the injection, that is, not yet the gene therapy).

A few weeks and one optic nerve injury later, these mice had more surviving nerve cells in their retinas than the control group did. In one final experiment, the scientists used whole retinas from mice removed two weeks after giving them a protrudin boost, to see if this treatment could prevent nerve cells from dying in the first place. The researchers found, three days later, that stimulating protrudin production had been almost “entirely neuroprotective, with these retinas exhibiting no loss of [retinal] neurons,” the researchers wrote in their paper. Usually, about half of retinal neurons removed in this way die within a couple of days.

“Our strategy relies on using gene therapy – an approach already in clinical use – to deliver protrudin into the eye,” said Veselina Petrova, a neuroscience student at the University of Cambridge. “It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow.”

Source: https://www.cam.ac.uk/