The amino acid transporter SLC 36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling

Summary The dry (nonneovascular) form of age‐related macular degeneration ( AMD ), a leading cause of blindness in the elderly, has few, if any, treatment options at present. It is characterized by early accumulation of cellular waste products in the retinal pigmented epithelium ( RPE ); rejuvenating impaired lysosome function in RPE is a well‐justified target for treatment. It is now clear that amino acids and vacuolar‐type H + ‐ ATP ase (V‐ ATP ase) regulate the mechanistic target of rapamycin, complex 1 ( mTORC 1) signaling in lysosomes. Here, we provide evidence for the first time that the amino acid transporter SLC 36A4/proton‐dependent amino acid transporter ( PAT 4) regulates the amino acid pool in the lysosomes of RPE . In Cryba1 (gene encoding βA3/A1‐crystallin) KO (knockout) mice, where PAT 4 and amino acid levels are increased in the RPE , the transcription factors EB ( TFEB ) and E3 ( TFE 3) are retained in the cytoplasm, even after 24 h of fasting. Consequently, genes in the coordinated lysosomal expression and regulation ( CLEAR ) network are not activated, and lysosomal function remains low. As these mice age, expression of RPE 65 and lecithin retinol acyltransferase ( LRAT ), two vital visual cycle proteins, decreases in the RPE . A defective visual cycle would possibly slow down the regeneration of new photoreceptor outer segments ( POS ). Further, photoreceptor degeneration also becomes obvious during aging, reminiscent of human dry AMD disease. Electron microscopy shows basal laminar deposits in Bruch's membrane, a hallmark of development of AMD . For dry AMD patients, targeting PAT 4/V‐ ATP ase in the lysosomes of RPE cells may be an effective means of preventing or delaying disease progression.