A team of researchers, led by scientists at the UC San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health, released findings Monday that may unlock a clue toward treating neurodegenerative diseases ranging from glaucoma to Alzheimer’s.
The team found that by inhibiting a particular family of enzymes, it may be possible to develop new therapies for treating diseases which 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.
According to the researchers, 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.
The multi-university team led by UCSD researchers identified another family of enzymes called germinal cell kinase four kinases whose inhibition is “robustly neuroprotective,” while also permitting axon regeneration, making it an attractive therapeutic approach for treating at some neurodegenerative diseases.
“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 Dr. Derek Welsbie, associate professor of ophthalmology at the 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,” Welsbie said.
The researchers — whose findings were published in the science journal PNAS — conducted a series of screens after first creating retinal ganglion cells from human stem cells. The cells are a type of neuron located near the inner surface of the retina of the eye. They receive visual information from photoreceptors and collectively help transmit that information to the brain.
The first screen involved testing a group of chemicals to assess their ability to increase the survival of the stem cells; the second to measure the ability of chemicals to promote regeneration.
“We then used a machine-learning technique to understand why certain compounds were active while others were not and it identified these key genes,” Welsbie said.
The discovery that these genes improved cell survival was not surprising, he said. What was surprising was the genes promoting regeneration.
Welsbie and colleagues focused their work on retinal ganglion cells because they are interested in optic diseases, such as glaucoma.
“Most people think only about glaucoma in terms of `eye pressure,”‘ Welsbie said.
But eye pressure is only part of the problem. Glaucoma is a neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons, leading to structural and functional damage to the optic nerve, visual impairment and blindness.
The U.S. Centers for Disease Control and Prevention estimate 3 million Americans have glaucoma. It is the second leading cause of blindness worldwide.
Welsbie cautioned that it’s not yet known whether the findings extend to other neuron types, but he noted that the work suggests strong therapeutic possibilities.
City News Service