期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 10, 页码 4045-4050出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1211284110
关键词
neuroprotection; MAP3K12; drug discovery
资金
- National Eye Institute
- NIH
- American Health Assistance Foundation
- Glaucoma Research Foundation
- Research to Prevent Blindness, Inc
- Macula Vision Research Foundation
- Eldon Family Foundation
- Vision for Children
- Grants-in-Aid for Scientific Research [21570184] Funding Source: KAKEN
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, non-glaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations.
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