Retinal oxidation, apoptosis and age- and sex-differences in the mnd mutant mouse, a model of neuronal ceroid lipofuscinosis.

Retinal degeneration is an early and progressive event in many forms of neuronal ceroid lipofuscinoses (NCLs), a heterogeneous group of neurodegenerative disorders with unknown pathogenesis. We here used the mutant motor neuron degeneration (mnd) mouse, a late-infantile NCL variant, to investigate the retinal oxidative state and apoptotic cell death as a function of age and sex. Total superoxide dismutase (SOD) activities and thiobarbituric acid-reactive substance (TBARS) levels revealed progressive increases in retinal oxyradicals and lipid peroxides of mnd mice of both sexes. Female mnd retinas showed a higher oxidation rate and consistently exhibited the 4-hydroxy-2-nonenal (4-HNE)-adducts staining and advanced histopathologic profile when compared to male mnd retinas matched for age. In situ DNA fragmentation (TUNEL staining) appeared in the outer nuclear layer (ONL) as early as 1 month of age. At 4 months, there were more intense and numerous TUNEL-positive cells in the same layer and in the inner nuclear (INL) and ganglion cell (GCL) layers; whereas at 8 months TUNEL staining was restricted to a few scattered cells in the INL and GCL, when a severe retinal cell loss had occurred. Caspase-3 activation confirmed apoptotic demise and its processing turned out to be higher in mnd females than males. These results demonstrate the involvement of oxidation and apoptotic processes in mnd mouse retinopathy and highlight sex-related differences in retinal vulnerability to oxidative stress and damage.