Aberrant early endosome biogenesis mediates complement activation in the retinal pigment epithelium in models of macular degeneration

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-09, Vol.115 (36), p.9014-9019
• Main Authors: Kaur, Gulpreet, Tan, Li Xuan, Rathnasamy, Gurugirijha, La Cunza, Nilsa, Germer, Colin J., Toops, Kimberly A., Fernandes, Marie, Blenkinsop, Timothy A., Lakkaraju, Aparna
• Format: Article
• Language: English
• Subjects: Age; Aged; Aged, 80 and over; Animal models; Animals; Antidepressants; ATP-Binding Cassette Transporters - deficiency; Autophagy; Biological Sciences; Biosynthesis; Ceramide; Ceramides - genetics; Ceramides - metabolism; Complement; Complement activation; Complement C3a - genetics; Complement C3a - metabolism; Complement component C3; Desipramine; Disease Models, Animal; Endosomes; Endosomes - genetics; Endosomes - metabolism; Endosomes - pathology; Epithelium; Female; Fragments; Humans; Image resolution; Internalization; Intracellular; Macular degeneration; Macular Degeneration - congenital; Macular Degeneration - genetics; Macular Degeneration - metabolism; Macular Degeneration - pathology; Male; Mice; Mice, Knockout; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Phagocytosis; Pigments; Proteins; Rapamycin; Retina; Retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Sphingomyelin phosphodiesterase; Swine; Therapeutic targets; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1805039115

Abnormally enlarged early endosomes (EEs) are pathological features of neurodegenerative diseases, yet insight into the mechanisms and consequences of EE expansion remains elusive. Here, we report swollen apical EEs in the retinal pigment epithelium (RPE) of aged human donors and in the pigmented Abca4 −/− mousemodel of Stargardt early-onset macular degeneration. Using high-resolution live-cell imaging, we show that age-related and pathological accumulation of lipofuscin bisretinoids increases ceramide at the apical surface of the RPE, which promotes inward budding and homotypic fusion of EEs. These enlarged endosomes internalize the complement protein C3 into the RPE, resulting in the intracellular generation of C3a fragments. Increased C3a in turn activates the mechanistic target of rapamycin (mTOR), a regulator of critical metabolic processes such as autophagy. The antidepressant desipramine, which decreases ceramide levels by inhibiting acid sphingomyelinase, corrects EE defects in the RPE of Abca4 −/− mice. This prevents C3 internalization and limits the formation of C3a fragments within the RPE. Although uncontrolled complement activation is associated with macular degenerations, how complement contributes to pathology in a progressive disease is not well understood. Our studies link expansion of the EE compartment with intracellular complement generation and aberrant mTOR activation, which could set the stage for chronic metabolic reprogramming in the RPE as a prelude to disease. The pivotal role of ceramide in driving EE biogenesis and fusion in the Abca4 −/− mice RPE suggests that therapeutic targeting of ceramide could be effective in Stargardt disease and other macular degenerations.