NSC PhD Defense Seminar: Kimberly Fernandes

The JNK Pathway is a Critical Regulator of Retinal Ganglion Cell Death Following Axonal Injury

Monday, November 4

9:00 AM10:00 AM MC 3-6408 (K-307)

Professor Richard T. Libby, Ph.D.

Abstract:

Glaucoma is the second leading cause of blindness worldwide and affects 6% of Americans over the age of 65. Glaucoma is characterized by the apoptotic death of retinal ganglion cells (RGCs) and optic nerve degeneration. There are no neuroprotective treatments for glaucoma and the disease is untreatable for many patients, underscoring the importance of identifying mechanisms that lead to RGC degeneration. Recent studies have shown that an important, initial site of injury to RGCs in glaucoma is to their axon as they exit the eye. Axon injury initiates a cascade of signaling events both proximally and distally to the site of insult to trigger somal and axonal degeneration respectively. The first sensors of axonal injury are hypothesized to be phosphorylation-dependent signal relay events that transduce the injury signal from the axon to the cell body. The c-Jun N-terminal kinase (JNK) family, encoded by Jnk1, Jnk2 and Jnk3, is known to play a critical role in retrograde axon injury signaling and regulate the transcriptional response to axon injury by activating transcription factors. Here, I examine the importance of the JNK signaling pathway in axonal injury induced RGC degeneration. I found that JNK2 and JNK3 are activated soon after axonal injury in RGC axons close to the site of insult and are critical for RGC death after axonal injury. JNK's canonical target, JUN, exerts a major pro-death role in RGCs by controlling key, early transcriptional responses to axonal injury, including prosurvival and proregenerative responses. Finally, to determine the kinase upstream of JNK activation, the importance of dual leucine zipper kinase (DLK) was tested. Dlk deficiency protects RGCs from axonal injury induced somal degeneration but not axonal degeneration. Interestingly, by carefully examining JNK activation after axonal injury in RGCs from Dlk and Jnk2/3 deficient mice, it became apparent that distinct upstream kinases regulate JNK activation in distinct cellular compartments of an RGC. Overall, these data highlight the importance of JNK signaling in diverse aspects of the RGC axonal injury response, including axon injury signaling and somal degeneration. Therefore inhibiting JNK activation might be an ideal target for therapeutic intervention in glaucoma.