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Significance Cell nonautonomous toxicity is involved in various neurodegenerations, but mechanistic understanding is limited. Here, we provide insight into cellular mechanisms underlying a dominant macular degeneration, which results from mutantELOVL4 , and represents an unusual case of two separate cell nonautonomous events. We demonstrate that the first event involves RPE phagocytosis of photoreceptor disc membranes that contain mislocalized mutant ELOVL4 protein. We show that the mutant phagosomes are degraded inefficiently, thus introducing toxicity to the RPE. This leads to the second event involving perturbed retinal homeostasis of the neural retina and photoreceptor degeneration. In addition, our results provide a unique demonstration that phagosome content affects phagosome motility and that the motility of the phagosome, specifically, may be critical for its timely degradation.

Defective phagosome motility and degradation in cell nonautonomous RPE pathogenesis of a dominant macular degeneration