PMID- 35939707
OWN - NLM
STAT- MEDLINE
DCOM- 20220810
LR  - 20230612
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 33
DP  - 2022 Aug 16
TI  - DARPP32, a target of hyperactive mTORC1 in the retinal pigment epithelium.
PG  - e2207489119
LID - 10.1073/pnas.2207489119 [doi]
LID - e2207489119
AB  - 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.
FAU - Cai, Jiyang
AU  - Cai J
AUID- ORCID: 0000-0003-4755-5452
AD  - Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma 
      City, OK 73104.
FAU - Litwin, Christopher
AU  - Litwin C
AD  - Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma 
      City, OK 73104.
AD  - Department of Ophthalmology, University of Oklahoma Health Sciences Center, 
      Oklahoma City, OK 73104.
FAU - Cheng, Rui
AU  - Cheng R
AD  - Department of Biochemistry, Wake Forest University Health Sciences, Winston 
      Salem, NC 27157.
FAU - Ma, Jian-Xing
AU  - Ma JX
AD  - Department of Biochemistry, Wake Forest University Health Sciences, Winston 
      Salem, NC 27157.
FAU - Chen, Yan
AU  - Chen Y
AUID- ORCID: 0000-0001-8451-5498
AD  - Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma 
      City, OK 73104.
AD  - Department of Ophthalmology, University of Oklahoma Health Sciences Center, 
      Oklahoma City, OK 73104.
AD  - Department of Biochemistry, University of Oklahoma Health Sciences Center, 
      Oklahoma City, OK 73104.
LA  - eng
GR  - R01 ES031980/ES/NIEHS NIH HHS/United States
GR  - P30 EY021725/EY/NEI NIH HHS/United States
GR  - R01 EY026999/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220808
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Dopamine and cAMP-Regulated Phosphoprotein 32)
RN  - 0 (PPP1R1B protein, human)
RN  - 0 (Ppp1r1b protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - *Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism
MH  - Enzyme Activation
MH  - Humans
MH  - *Macular Degeneration/metabolism
MH  - *Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mice
MH  - Retina/metabolism
MH  - *Retinal Pigment Epithelium/metabolism
MH  - Signal Transduction
PMC - PMC9388070
OTO - NOTNLM
OT  - RPE
OT  - age-related macular degeneration
OT  - drusen
OT  - mTORC1
COIS- Competing interest statement: J.-X.M. is a cofounder of Excitant.
EDAT- 2022/08/09 06:00
MHDA- 2022/08/11 06:00
PMCR- 2022/08/08
CRDT- 2022/08/08 15:23
PHST- 2022/08/08 15:23 [entrez]
PHST- 2022/08/09 06:00 [pubmed]
PHST- 2022/08/11 06:00 [medline]
PHST- 2022/08/08 00:00 [pmc-release]
AID - 202207489 [pii]
AID - 10.1073/pnas.2207489119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2207489119. doi: 
      10.1073/pnas.2207489119. Epub 2022 Aug 8.