advertisement
Abstract #52959 Published in IGR 15-1
Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death
Welsbie DS; Yang Z; Ge Y; Mitchell KL; Zhou X; Martin SE; Berlinicke CA; Hackler L; Fuller J; Fu J; Cao LH; Han B; Auld D; Xue T; Hirai S; Germain L; Simard-Bisson C; Blouin R; Nguyen JV; Davis CH; Enke RA; Boye SL; Merbs SL; Marsh-Armstrong N; HauswirthProceedings of the National Academy of Sciences of the United States of America 2013; 110: 4045-4050
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.
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Full articleClassification:
11.8 Neuroprotection (Part of: 11 Medical treatment)
3.6 Cellular biology (Part of: 3 Laboratory methods)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
