气候变化领域集成服务门户(CCPortal): Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons

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DOI	10.1073/PNAS.2004683117
	Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons
	Patel A.K.; Broyer R.M.; Lee C.D.; Lu T.; Louie M.J.; Torre A.L.; Al-Ali H.; Vu M.T.; Mitchell K.L.; Wahlin K.J.; Berlinicke C.A.; Jaskula-Ranga V.; Hu Y.; Duan X.; Vilar S.; Bixby J.L.; Weinreb R.N.; Lemmon V.P.; Zack D.J.; Welsbie D.S.
发表日期	2021
ISSN	00278424
起始页码	33597
结束页码	33607
卷号	117 期号:52
英文摘要	Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as a key mediator of this process. However, while DLK inhibition is robustly protective in a wide range of neurodegenerative disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that are known to both improve long-term survival and promote regeneration. To identify such a neuroprotective target, we conducted a set of complementary high-throughput screens using a protein kinase inhibitor library in human stem cell-derived retinal ganglion cells (hRGCs). Overlapping compounds that promoted both neuroprotection and neurite outgrowth were bioinformatically deconvoluted to identify specific kinases that regulated neuronal death and axon regeneration. This work identified the role of germinal cell kinase four (GCK-IV) kinases in cell death and additionally revealed their unexpected activity in suppressing axon regeneration. Using an adeno-associated virus (AAV) approach, coupled with genome editing, we validated that GCK-IV kinase knockout improves neuronal survival, comparable to that of DLK knockout, while simultaneously promoting axon regeneration. Finally, we also found that GCK-IV kinase inhibition also prevented the attrition of RGCs in developing retinal organoid cultures without compromising axon outgrowth, addressing a major issue in the field of stem cell-derived retinas. Together, these results demonstrate a role for the GCK-IV kinases in dissociating the cell death and axonal outgrowth in neurons and their druggability provides for therapeutic options for neurodegenerative diseases. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Axon regeneration; GCK-IV kinases; Neuroprotection
语种	英语
scopus关键词	protein kinase inhibitor; animal; axon; C57BL mouse; cell death; cell survival; central nervous system; CRISPR Cas system; Dependoparvovirus; disease model; drug effect; enzymology; genetics; human; metabolism; nerve regeneration; neurite outgrowth; nucleotide sequence; optic nerve injury; organoid; pathology; retina ganglion cell; signal transduction; Animals; Axons; Base Sequence; Cell Death; Cell Survival; Central Nervous System; CRISPR-Cas Systems; Dependovirus; Disease Models, Animal; Germinal Center Kinases; Humans; Mice, Inbred C57BL; Nerve Regeneration; Neuronal Outgrowth; Optic Nerve Injuries; Organoids; Protein Kinase Inhibitors; Retinal Ganglion Cells; Signal Transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179664
作者单位	Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California San Diego, San Diego, CA 92093, United States; Department of Cell Biology and Human Anatomy, University of California, Davis, CA 95616, United States; Truvitech LLC, Miami, FL 33136, United States; Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami, Miami, FL 33136, United States; Peggy and Hardol Katz Family Drug Discovery Center, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, United States; Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, United States; Department of Ophthalmology, Stanford University, Stanford, CA 94304, United States; Department of Ophthalmology, University of California, San Francisco, CA 94158, United States; Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33136, United States; Center for Computational Sciences, University of Miami, Miami, F...
推荐引用方式 GB/T 7714	Patel A.K.,Broyer R.M.,Lee C.D.,et al. Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons[J],2021,117(52).
APA	Patel A.K..,Broyer R.M..,Lee C.D..,Lu T..,Louie M.J..,...&Welsbie D.S..(2021).Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Patel A.K.,et al."Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).