ERK1/2 pathway is activated in degenerated Rpe65-deficient mice

The MAPK family is composed of three majors kinases, JNK, p38 and ERK1/2, and is implicated in many degenerative processes, including retinal cell death. The purpose of our study was to evaluate the activation of ERK1/2 kinase, and its potential role in Muller cell gliosis, during photoreceptor cell death in Rpe65(-/-) mice. We assayed ERK1/2 mRNA and protein levels, and evaluated ERK1/2 phosphorylation involved in kinase activation, in 2,4 and 6 month-old Rpe65(-/-) mice and in age-matched wild-type controls. No differences in ERK1/2 expression were detected between Rpe65(-/-) and wild-type mice, however, ERK1/2 phosphorylation was dramatically increased in the knock out mice at 4 and 6 months-of-age. Phosphorylated ERK1/2 co-localized with GFAP in the ganglion cell layer, and correlated with an increase in GFAP protein expression and retinal cell death. Accumulation of cFOS protein in the ganglion cell layer occurred concomitant with pERK1/2 activation. Muller cell proliferation was not observed. ERK1/2 activation did not occur in 2 month-old Rpe65(-/-) or in the Rpe65(-/-)/Gnat1(-/-) mice, in which no degeneration was evident. The observed activation ERK1/2 and GFAP, both markers of Muller cell gliosis, in the absence of Muller cell proliferation, is consistent with the activation of atypical gliosis occurring during the slow process of degeneration in Rpe65(-/-) mice. As Muller cell gliosis is activated in many neuronal and retinal degenerative diseases, further studies will be needed to determine whether atypical gliosis in Rpe65(-/-) mice contributes to, or protects against, the pathogenesis occurring in this model of Leber congenital amaurosis. (C) 2013 Elsevier Ltd. All rights reserved.