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DARPP32, a target of hyperactive mTORC1 in the retinal pigment epithelium
Jiyang Cai1, Christopher Litwin2,3, Rui Cheng4
1Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
Abstract:
The mechanistic target of rapamycin (mTOR) is assembled into signaling complexes of mTORC1 or mTORC2, and plays key roles in cell metabolism, stress response, and nutrient and growth factor sensing. Accumulating evidence from human and animal model studies has demonstrated a pathogenic role of hyperactive mTORC1 in age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) is a primary injury site in AMD. In mouse models of RPE-specific deletion of Tuberous sclerosis 1 (Tsc1), which encodes an upstream suppressor of mTORC1, the hyperactivated mTORC1 metabolically reprogrammed the RPE and led to the degeneration of the outer retina and choroid (CH). In the current study, we use single-cell RNA sequencing (scRNA-seq) to identify an RPE mTORC1 downstream protein, dopamine- and cyclic AMP-regulated phosphoprotein of molecular weight 32,000 (DARPP-32). DARPP-32 was not found in healthy RPE but localized to drusen and basal linear deposits in human AMD eyes. In animal models, overexpressing DARPP-32 by adeno-associated virus (AAV) led to abnormal RPE structure and function. The data indicate that DARPP-32 is a previously unidentified signaling protein subjected to mTORC1 regulation and may contribute to RPE degeneration in AMD.
Insights
Hyperactive mTORC1 signaling in retinal pigment epithelium (RPE) drives age-related macular degeneration (AMD). Researchers identified DARPP-32 as a novel mTORC1 target protein contributing to RPE degeneration in AMD.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Medicine
Background:
- The mechanistic target of rapamycin (mTOR) pathway, specifically mTORC1, is implicated in age-related macular degeneration (AMD) pathogenesis.
- Hyperactive mTORC1 signaling in the retinal pigment epithelium (RPE) contributes to AMD progression.
Purpose of the Study:
- To identify novel downstream targets of mTORC1 in the RPE relevant to AMD.
- To investigate the role of dopamine- and cyclic AMP-regulated phosphoprotein of molecular weight 32,000 (DARPP-32) in RPE degeneration.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was employed to identify mTORC1-regulated proteins in RPE.
- Immunohistochemistry was used to localize DARPP-32 in human AMD eyes and animal models.
- Adeno-associated virus (AAV) mediated overexpression of DARPP-32 in animal models.
Main Results:
- DARPP-32 was identified as an mTORC1 downstream protein in RPE, absent in healthy RPE but present in AMD lesions.
- Overexpression of DARPP-32 in mouse models induced RPE dysfunction and structural abnormalities.
- These findings link mTORC1 dysregulation to specific molecular changes in RPE relevant to AMD.
Conclusions:
- DARPP-32 is a novel, mTORC1-regulated protein implicated in RPE degeneration.
- DARPP-32 may represent a potential therapeutic target for age-related macular degeneration.
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