New Discovery on How to Protect Neurons and Encourage Their Growth

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Retinal Ganglion Cell

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Example of retinal ganglion cells with axons and dendrites in the retina of a healthy eye. Credit: UC San Diego Health Sciences

By hindering a specific household of enzymes, it might be possible to establish brand-new treatments for dealing with neurodegenerative illness from glaucoma to Alzheimer’s.

Many neurodegenerative conditions, from glaucoma to Alzheimer’s illness, are identified by injury to axons — the long, slim forecasts that perform electrical impulses from one afferent neuron to another, helping with cellular interactions. Injury to axons typically causes neuronal disability and cell death. 

Researchers understand that hindering an enzyme called double leucine zipper kinase (DLK) appears to robustly safeguard nerve cells in a vast array of neurodegenerative illness designs, however DLK likewise hinders axonal regrowth. Until now, there have actually been no reliable approaches to customize genes to enhance both the long-lasting survival of nerve cells and promote regrowth.

In a paper released on December 14, 2020, in Proceedings of the National Academy of Sciences (PNAS), a multi-university group led by scientists at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health determined another household of enzymes called germinal cell kinase 4 kinases (GCK-IV kinases) whose inhibition is robustly neuroprotective, while likewise allowing axon regrowth, making it an appealing healing technique for dealing with at some neurodegenerative illness.

“We basically figured out that there are a set of genes that, when inhibited, allow optic nerve cells to survive and regenerate,” stated senior author Derek Welsbie, MD, PhD, associate teacher 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.” 

The scientists performed a series of screens after very first developing retinal ganglion cells (RGC) from human stem cells. RGCs are a kind of nerve cell situated near the inner surface area of the retina of the eye. They get visual info from photoreceptors and jointly assist send that info to the brain.

The very first screen included evaluating a group of well-studied chemicals to evaluate their capability to increase the survival of RGCs; the 2nd to determine the capability of chemicals to promote regrowth. 

“We then used a machine-learning technique to understand why certain compounds were active while others were not and it identified these key genes,” stated Welsbie.

The discovery that these genes enhanced RGC survival was not unexpected, he stated. “However, you would have predicted that they (like DLK) would have blocked regeneration when inhibited, not promote regeneration. That was definitely a surprise. It highlights one of the advantages of discovery-based science using high-throughput screening: By testing many agents at once, we can find identify overlooked genes that might not have been thought to play a role.”

Welsbie and coworkers focused their deal with RGCs due to the fact that they have an interest in optic neuropathies, such as glaucoma. “Most people think only about glaucoma in terms of ‘eye pressure,’” Welsbie stated. But eye pressure is just part of the issue. At its core, glaucoma is a neurodegenerative illness identified by progressive loss of RGCs and their axons, resulting in quantifiable structural and practical damage to the optic nerve, visual disability, and loss of sight. 

The U.S. Centers for Disease Control and Prevention quote 3 million Americans have glaucoma. It is the 2nd leading reason for loss of sight worldwide. 

Welsbie warned that it’s not yet understood whether these findings reach other nerve cell types, however he kept in mind that the work recommends strong healing possibilities. 

Reference: “Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons” by Amit K. Patel, Risa M. Broyer, Cassidy D. Lee, Tianlun Lu, Mikaela J. Louie, Anna La Torre, Hassan Al-Ali, Mai T. Vu, Katherine L. Mitchell, Karl J. Wahlin, Cynthia A. Berlinicke, Vinod Jaskula-Ranga, Yang Hu, Xin Duan, Santiago Vilar, John L. Bixby, Robert N. Weinreb, Vance P. Lemmon, Donald J. Zack and Derek S. Welsbie, 14 December 2020, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2004683117

Co-authors consist of: Amit K. Patel, Risa M. Broyer, Cassidy D. Lee, Tianlun Lu, Mai T. Vu, Karl J. Wahlin and Robert N. Weinreb, all at UC San Diego; Mikaela J. Louie, Anna La Torre and Yang Hu, UC Davis; Hassan Al-Ali, John L. Bixby and Vance P. Lemmon, University of Miami; Katherine L. Mitchell and Vinod Jaskula-Ranga and Donald J. Zack, Johns Hopkins University; Xin Duan, UC San Francisco; Santiago Vilar, Truvitech, Miami.

Funding for this research study came, in part, from the National Institutes of Health (grant 1RO1EY029342), Research to Prevent Blindness, E. Matilda Ziegler Foundation, Brightfocus Foundation, Fight for Sight Foundation, the Glaucoma Research Foundation Catalyst for the Cure and the Tushinsky household.