title: Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death.
abstract: Glaucoma, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, nonglaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations.
authors: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Derek S
authors: DS
authors: Welsbie
authors: Zhiyong
authors: Z
authors: Yang
authors: Yan
authors: Y
authors: Ge
authors: Katherine L
authors: KL
authors: Mitchell
authors: Xinrong
authors: X
authors: Zhou
authors: Scott E
authors: SE
authors: Martin
authors: Cynthia A
authors: CA
authors: Berlinicke
authors: Laszlo
authors: L
authors: Hackler
authors: John
authors: J
authors: Fuller
authors: Jie
authors: J
authors: Fu
authors: Li-hui
authors: LH
authors: Cao
authors: Bing
authors: B
authors: Han
authors: Douglas
authors: D
authors: Auld
authors: Tian
authors: T
authors: Xue
authors: Syu-ichi
authors: S
authors: Hirai
authors: Lucie
authors: L
authors: Germain
authors: Caroline
authors: C
authors: Simard-Bisson
authors: Richard
authors: R
authors: Blouin
authors: Judy V
authors: JV
authors: Nguyen
authors: Chung-ha O
authors: CH
authors: Davis
authors: Raymond A
authors: RA
authors: Enke
authors: Sanford L
authors: SL
authors: Boye
authors: Shannath L
authors: SL
authors: Merbs
authors: Nicholas
authors: N
authors: Marsh-Armstrong
authors: William W
authors: WW
authors: Hauswirth
authors: Aaron
authors: A
authors: DiAntonio
authors: Robert W
authors: RW
authors: Nickells
authors: James
authors: J
authors: Inglese
authors: Justin
authors: J
authors: Hanes
authors: King-Wai
authors: KW
authors: Yau
authors: Harry A
authors: HA
authors: Quigley
authors: Donald J
authors: DJ
authors: Zack
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D005901:Glaucoma / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D009901:Optic Nerve Diseases / Q000209:etiology / Q000473:pathology; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D015398:Signal Transduction; D015854:Up-Regulation; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D020930:MAP Kinase Kinase Kinases; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C090757:mitogen-activated protein kinase kinase kinase 12