Abstract
Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy.
Highlights
Neuronal ceroid lipofuscinoses (NCLs) describes a group of genetically distinct neurodegenerative lysosomal storage diseases that involve excessive accumulation of lipofuscin
We propose that CLN3 is localized to apical microvilli of retinal pigment epithelium (RPE) and is essential for crucial structure (RPE microvilli) and function (POS phagocytosis) of RPE cells that are vital for photoreceptor survival and vision
Using human induced pluripotent stem cell (hiPSC)-RPE from patients harboring a homozygous 966 bp deletion spanning exon 7 and 8, the most common mutation in CLN3 disease, we show that disease-causing CLN3 mutations in CLN3 disease affect both RPE cell structure and function in a cell autonomous manner
Summary
Neuronal ceroid lipofuscinoses (NCLs) describes a group of genetically distinct neurodegenerative lysosomal storage diseases that involve excessive accumulation of lipofuscin. It is well established that retinal damage is responsible for vision loss in CLN3 disease, the primary cellular and molecular mechanisms leading to retinal degeneration in CLN3 disease are not known. The RPE in CLN3 disease has notably low levels of lipofuscin[13,14], even though it still undergoes atrophy[13] One explanation for this apparent paradox is that loss of vision in CLN3 disease patients starts at a young age (5–10 years old5), with reduced rod and cone responses[2,20,21] and photoreceptor cell loss[2,21,22], and that the low levels of lipofuscin in the RPE result from the presence of fewer photoreceptors. It is plausible that RPE cells fail to take up POS in CLN3 disease This hypothesis could explain the increased autofluorescence accumulation observed in the photoreceptor layer (presence of POS debris) and photoreceptor loss in CLN3 disease[1,21,27,28]
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