DARPP-32, a new player in the pathogenesis of Age-related macular degeneration?

What is it about?

Age-related macular degeneration (AMD) is a common cause of blindness and currently has no effective treatment. In recent years we and others have found that overactivation of the signaling pathways mediated by mTORC1 is a pathogenic mechanism of AMD. In the paper, we identified a target protein of mTORC1, DARPP32, that is unique to the diseased retinal pigment epithelium (RPE).

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Why is it important?

AMD is a multifactorial disease; and mTOR is a sensor protein that connects environmental and stress conditions to RPE metabolic regulation. Abnormaly high mTORC1 activity is detrimental to RPE health. To develop mechanism-based therapy for such a chronic disease, a key challenge is to define druggable targets that are restricted to the diseased RPE cells. Our current study demonstrated that the DARPP-32 protein had low abundance in healthy RPE but was markedly upregulated by hyperactivated mTOR in degenerating RPE cells and accumulated in the drusen, a hallmarker feature of AMD. Inhibiting mTORC1 by rapamycin reduced DARPP-32 to its basal level, while overexpressing the protein with adeno-associated viral vector compromised RPE barrier function. The findings revealed a previously unrecognized protein that likely contributes to the development of RPE degeneration in AMD.