PMID- 36934843
OWN - NLM
STAT- MEDLINE
DCOM- 20230526
LR  - 20230701
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 64
IP  - 5
DP  - 2023 May
TI  - Ablation of pigment epithelium-derived factor receptor (PEDF-R/Pnpla2) causes 
      photoreceptor degeneration.
PG  - 100358
LID - S0022-2275(23)00031-7 [pii]
LID - 10.1016/j.jlr.2023.100358 [doi]
LID - 100358
AB  - Photoreceptor cells express the patatin-like phospholipase domain-containing 2 
      (PNPLA2) gene that codes for pigment epithelium-derived factor receptor (PEDF-R) 
      (also known as ATGL). PEDF-R exhibits phospholipase activity that mediates the 
      neurotrophic action of its ligand PEDF. Because phospholipids are the most 
      abundant lipid class in the retina, we investigated the role of PEDF-R in 
      photoreceptors by generating CRISPR Pnpla2 knock-out mouse lines in a retinal 
      degeneration-free background. Pnpla2(-/-) mice had undetectable retinal Pnpla2 
      gene expression and PEDF-R protein levels as assayed by RT-PCR and 
      immunofluorescence, respectively. The photoreceptors of mice deficient in PEDF-R 
      had deformities as examined by histology and transmission electron microscopy. 
      Pnpla2 knockdown diminished the PLA(2) enzymatic activity of PEDF-R in the 
      retina. Lipidomic analyses revealed the accumulation of lysophosphatidyl 
      choline-DHA and lysophosphatidyl ethanolamine-DHA in PEDF-R-deficient retinas, 
      suggesting a possible causal link to photoreceptor dysfunction. Loss of PEDF-R 
      decreased levels of rhodopsin, opsin, PKCalpha, and synaptophysin relative to 
      controls. Pnpla2(-/-) photoreceptors had surface-exposed phosphatidylserine, and 
      their nuclei were TUNEL positive and condensed, revealing an apoptotic onset. 
      Paralleling its structural defects, PEDF-R deficiency compromised photoreceptor 
      function in vivo as indicated by the attenuation of photoreceptor a- and b-waves 
      in Pnpla2(-/-) and Pnpla2(+/-) mice relative to controls as determined by 
      electroretinography. In conclusion, ablation of PEDF-R in mice caused alteration 
      in phospholipid composition associated with malformation and malperformance of 
      photoreceptors. These findings identify PEDF-R as an important component for 
      photoreceptor structure and function, highlighting its role in phospholipid 
      metabolism for retinal survival and its consequences.
CI  - Published by Elsevier Inc.
FAU - Bernardo-Colon, Alexandra
AU  - Bernardo-Colon A
AD  - Section of Protein Structure and Function, Laboratory of Retinal Cell and 
      Molecular Biology, National Eye Institute, National Institutes of Health, 
      Bethesda, MD, USA.
FAU - Dong, Lijin
AU  - Dong L
AD  - Genetic Engineering Core, National Eye Institute, National Institutes of Health, 
      Bethesda, MD, USA.
FAU - Abu-Asab, Mones
AU  - Abu-Asab M
AD  - Histopathology Core Facility, National Eye Institute, National Institutes of 
      Health, Bethesda, MD, USA.
FAU - Brush, Richard S
AU  - Brush RS
AD  - Department of Ophthalmology(,) and Dean A. McGee Eye Institute, Oklahoma City, 
      OK, USA.
FAU - Agbaga, Martin-Paul
AU  - Agbaga MP
AD  - Department of Ophthalmology(,) and Dean A. McGee Eye Institute, Oklahoma City, 
      OK, USA; Department of Cell Biology, University of Oklahoma Health Sciences 
      Center, Oklahoma City, OK, USA.
FAU - Becerra, S Patricia
AU  - Becerra SP
AD  - Section of Protein Structure and Function, Laboratory of Retinal Cell and 
      Molecular Biology, National Eye Institute, National Institutes of Health, 
      Bethesda, MD, USA. Electronic address: becerras@nei.nih.gov.
LA  - eng
GR  - R01 EY030513/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230317
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (pigment epithelium-derived factor receptor)
RN  - 0 (Eye Proteins)
RN  - 0 (Serpins)
RN  - 0 (Nerve Growth Factors)
RN  - EC 3.1.- (Phospholipases)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Eye Proteins/genetics/metabolism
MH  - *Serpins/genetics/metabolism
MH  - Nerve Growth Factors/genetics/metabolism
MH  - *Retinal Degeneration/genetics/metabolism/pathology
MH  - Retina/metabolism
MH  - Phospholipases/metabolism
PMC - PMC10233210
OTO - NOTNLM
OT  - Eye
OT  - PEDF-R/ATGL
OT  - Pnpla2
OT  - eye/retina
OT  - phospholipase A2
OT  - phospholipids
OT  - photoreceptors
OT  - retina
COIS- Conflict of interest none.
EDAT- 2023/03/20 06:00
MHDA- 2023/05/26 06:42
PMCR- 2023/03/17
CRDT- 2023/03/19 20:28
PHST- 2022/12/14 00:00 [received]
PHST- 2023/03/03 00:00 [revised]
PHST- 2023/03/04 00:00 [accepted]
PHST- 2023/05/26 06:42 [medline]
PHST- 2023/03/20 06:00 [pubmed]
PHST- 2023/03/19 20:28 [entrez]
PHST- 2023/03/17 00:00 [pmc-release]
AID - S0022-2275(23)00031-7 [pii]
AID - 100358 [pii]
AID - 10.1016/j.jlr.2023.100358 [doi]
PST - ppublish
SO  - J Lipid Res. 2023 May;64(5):100358. doi: 10.1016/j.jlr.2023.100358. Epub 2023 Mar 
      17.