Abstract Details

Title Deficiency of Mkk4 and Mkk7 Together Prevents Both Retinal Ganglion Cell Death and Axonal Degeneration After Axonal Injury

Topic Neuro-ophthalmology/Neuro-otology

Presentation(s) S32 - Neuro-ophthalmology/Neuro-otology (4:30 PM-4:42 PM)

Poster/Presentation
Number 006

Objective To identify molecules critical for retinal ganglion cell death (RGC) and axonal degeneration after axonal injury.

Background Optic nerve injury is an important component of traumatic, inflammatory, ischemic, and glaucomatous optic neuropathies. The mitogen activated protein kinase (MAPK) signaling pathways are important for neurodegeneration. Deficiency of either MKK4 or MKK7, MAPK signaling members, have been shown to provide mild protection to RGC somas and their axons but have not been tested together in an in-vivo model of injury.

Design/Methods An intravitreal injection was used to deliver active AAV2.2-CMV-Cre-GFP or control AAV2.2-CMV-GFP into eyes of mice homozygous for floxed alleles of both Mkk4 and Mkk7 (Mkk4/7 deficient). After 28 days for RGC transduction and recombination, mechanical controlled optic nerve crush (CONC) was performed and immunohistochemistry was used to assess RGC survival.

Results AAV-CMV-Cre-GFP mediated deletion of Mkk4/7 did not alter RGC survival 75 days after injection as compared to control AAV-CMV-GFP injected or noninjected eyes in non-injured retinas (p=0.52, n=4). After CONC, Mkk4/7 deficiency did significantly alter RGC survival. Mkk4/7 deficient retinas had 91.4% fewer RGCs expressing pJUN, the downstream target of MKK4/7 (p<0.0001, n≥6). Dual Mkk4/7 deficient retinas had 85.6% fewer cleaved-caspase-3 dying RGCs 5 days after CONC (p<0.0001; n≥10) and a greater percentage of surviving RGCs 14 days after CONC as compared to control retinas (WT: 20.1% survival, Mkk4/7: 91.8%; p<0.0001; n≥8). Longitudinal sections of distal optic nerve demonstrated preserved axonal integrity in Mkk4/7 deficient retinas 5 days after CONC as compared to axonal fragmentation and beading in control nerves (n=4).

Conclusions Combined deficiency of Mkk4 and Mkk7 provided robust, almost complete protection to RGC somas and slowed axon degeneration distal to the site of injury. Together, these data suggest these molecules are excellent targets for mitigating axonal injury-mediated neurodegeneration because they contribute to both the somal and axonal compartment of neurodegeneration.

Authors/Disclosures
Stephanie Syc-Mazurek, MD, PhD (Mayo Clinic) PRESENTER	Dr. Syc-Mazurek has a non-compensated relationship as a Editorial Board Resident and Fellows Section with Neurology that is relevant to AAN interests or activities.
	No disclosure on file
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