internalized rhodopsin in dying photoreceptor cells were not degraded but instead showed characteristics of insoluble proteins. This data led to the implication of rhodopsin buildup in the late endosomal system as a novel trigger of death of photoreceptor neurons. Thus failure to degrade internalized rhodopsin in a timely manner triggers cell death of photoreceptor neurons, suggesting that lysosomal turnover of rhodopsin is vital in maintaining photoreceptor viability. The precise mechanisms regulating the pro-cell death signaling pathways and their interconnection with endocytosis is not well understood. It is speculated that a component innate to the endolysosomal system plays a crucial role in regulating the cell death signals emanating from the endosomes. This component senses the accumulation of rhodopsin and then engages the proper machinery to execute cell death in the retina. Failure of proper protein degradation and resultant subsequent accumulation of proteins, as in the case of rhodopsin-arrestin complexes, is a well-recognized cause of cell death in many neurodegenerative disorders, such as retinitis pigmentosa. Non-rhodopsin mutations Mutations non-retina-specific ADRP genes that encode for proteins essential for pre-mRNA splicing may be a major cause of ADRP. Proteins required for the formation of stable U4/U6 snRNPs and for assembly of the U4/U6.U5 tri-snRNP have been identified, including HPRP3, PRPC8, and PRPF31, proper function of these proteins is necessary for spliceosome performance. The rhodopsin transcript is a pre-mRNA splicing substrate affected by PRPF31 protein, meaning that rhodopsin (RHO) is among the target splicing substrate genes for PRPF31. Thus it can be understood that mutations in PRPF31 can cause alternative, potentially non-functional, forms of the rhodopsin protein. It was shown that expression of these mutant PRPF31 proteins significantly reduced rhodopsin expression in cultured retinal cells and induced apoptosis of retinal cells, establishing a link between mutations in proteins involved in pre-mRNA splicing and the expression of a critical retina-specific gene, rhodopsin. This shows that non-rhodopsin mutations may also be critical in presentation of retinal degenerative disorders. It suggests a mechanism for retinal degeneration caused by non-retinal-specific genes, such as PRPF31 mutations. Notes References Eye diseases