TNF-alpha and TNF receptor 1 in retinal and optic nerve degeneration of the CLN8 mutant mouse.

Loss of visual function is a clue in many forms of neuronal ceroid lipofuscinoses (NCLs), a group of inherited neurodegenerative diseases characterised by epilepsy and psychomotor deterioration. Mutations in at least eight different genes have been identified and all forms display a typical accumulation of autofluorescent storage material, but their pathogenesis is still undefined. Recent evidence correlates inflammation to brain and spinal cord dysfunction in some NCL forms, including the mnd mouse model bearing a spontaneous mutation of CLN8 gene linked to the human NCL form EPMR. In the mnd mouse, we have also reported that retinal degeneration is accompanied by oxidative changes and apoptotic death. Here, to assess whether there is an inflammatory component to visual loss, the TNF receptor system along with morphological changes in glial compartment were studied in the retina and optic nerve of mnd mice at different ages. A progressive increase in local microglia activation/expansion and astroglia was found in mnd retina and optic nerve, as detected through immunostaining with F4/80 and GFAP. Activated microglia appeared to precede retinal massive astroglial proliferation and neuron degeneration, and was mostly confined to the ganglion cell layer by 1 month and to the outer nuclear layer by 3 months of age. In the optic nerve, electron microscopy exhibited glial hypertrophy concomitantly to different stages of axonal and myelin degeneration by 2 months. In both structures, levels of TNF-alpha and TNF receptor 1 were found to be highly expressed at 1 and 3 months, with the highest expression at 1 month of age. Cleavage of caspase-8 and caspase-3 appeared as early as 1 month of age in mnd retinas, but only at 3 months in the optic nerve. The results demonstrate a role of inflammation in visual loss as well as in brain and spinal cord dysfunction, and they additionally provide evidence for the implication of TNF death receptor signaling in the pathology of NCLs.