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

ABSTRACT: 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^-/- mouse model 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 m

SUBMITTER: Kaur G 

PROVIDER: S-EPMC6130344 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature