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

Significance The first lines of communication between cells and the environment are early endosomes, which sort incoming cargo to regulate cell health. Endosomal abnormalities are seen in neurodegenerative diseases, yet the molecular mechanisms remain obscure. Here, using human donor cells and disease models, we demonstrate that excess ceramide promotes expansion of early endosomes in the retinal pigment epithelium (RPE), a primary site of injury in Stargardt and age-related maculopathies. Complement C3 uptake into enlarged endosomes and subsequent cleavage is associated with abnormal mechanistic target of rapamycin activity. Decreasing ceramide using Food and Drug Administration-approved drugs corrects endosomal defects and prevents C3 activation. Our studies establish how organelles modulate RPE complement activity, and identify ceramide as a drug target for macular degenerations.