Incomplete proteolysis may contribute to lipofuscin accumulation in the retinal pigment epithelium

A substantial amount of experimental evidence indicates that the bulk of retinal pigment epithelial (RPE) lipofuscin is derived from components of the photoreceptor outer segments. Antioxidant nutrient deficiency promotes RPE lipofuscin deposition, suggesting that oxidation of outer segment components is involved in the formation of this pigment. However, the fluorescent products of in vitro oxidation of retinal constituents differ from the fluorophores associated with lipofuscin. Thus, the role of nonenzymatic oxidation in lipofuscin formation is probably indirect; it may inhibit proteolysis, which in turn allows nonoxidative amino acid modifications to accumulate. Direct inhibition of proteolysis by the RPE in vivo results in a rapid appearance of lipofuscin-like fluorescence in the undegraded proteins. This suggests that protein components of the outer segments are probably the major precursors of RPE lipofuscin. The modifications undergone by these proteins that are responsible for their accumulation in the RPE and for lipofuscin fluorescence remain to be determined.