Park7 protects retinal ganglion cells and promotes functional preservation after optic nerve crush via regulation of the Nrf2 signaling pathway

Purpose: We aim to investigate the effect of Park7 on mice RGC survival and function following optic nerve crush (ONC), and to explore its potential mechanism.

Methods: Wild-type male C57BL/6J mice were subjected to optic nerve crush. Six weeks before ONC, mice received rAAV-shRNA (Park7)-EGFP or rAAV-EGFP intravitreally. Western blotting was used to detect Park7 levels. RGC survival was measured using immunofluorescence. Retinal cell apoptosis was detected using terminal deoxynucleotidyl transferase nick-end-labelling. An electroretinogram (ERG) and the optomotor response (OMR) were used to assess RGC function. Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor (Nrf2), and heme oxygenase 1 (HO-1) levels were assessed using western blotting.

Results: ONC injury increased the relative expression of Park7 significantly and decreased RGC survival, the amplitude of the photopic negative response (PhNR), and OMR. Intravitreal injection of rAAV-shRNA(Park7)-EGFP downregulated Park7 expression and was clearly demonstrated by the green fluorescence protein in many retinal layers. Moreover, Park7 downregulation aggravated the decrease in RGC survival and amplitude of PhNR as well as the visual acuity after ONC. However, inhibition of Park7 significantly increased Keap1 levels, decreased the total and nuclear Nrf2 levels, and reduced HO-1 levels.

Conclusions: Park7 downregulation enhanced RGC injury and decreased retinal electrophysiological response and OMR after ONC in mice via the Keap1-Nrf2-HO-1 signaling pathway. Park7 may have neuroprotective effects and could represent a novel way to treat optic neuropathy.