Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina.

Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and degradation of photoreceptor outer segments by the postmitotic retinal pigment epithelium (RPE) are essential for healthy vision.

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration.

Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet mechanisms linking risk variants to RPE injury remain unclear. We sought to determine how allelic variants in the apolipoprotein E cholesterol transporter modulate RPE homeostasis and function.

Complement activation, lipid metabolism, and mitochondrial injury: Converging pathways in age-related macular degeneration.

The retinal pigment epithelium (RPE) is the primary site of injury in non-neovascular age-related macular degeneration or dry AMD. Polymorphisms in genes that regulate complement activation and cholesterol metabolism are strongly associated with AMD, but the biology underlying disease-associated variants is not well understood. Here, we highlight recent studies that have used molecular, biochemical, and live-cell imaging methods to elucidate mechanisms by which aging-associated insults conspire with AMD genetic risk variants to tip the balance towards disease.

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

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 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.

Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis.

Objective: We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue.

Design: Mice were treated with the pan-Notch inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches.