Biology subjects

Becerra, S. P.

Publications and source records attributed to Becerra, S. P..

4 recordsLinked to original sources

bioRxiv2026

PEDF/PEDF-R Signaling Regulates Retinal Phospholipid Homeostasis and Photoreceptor Survival

Pigment epithelium-derived factor (PEDF) promotes photoreceptor survival through its receptor PEDF-R, a phospholipase involved in retinal lipid metabolism. To define the in vivo function of the PEDF/PEDF-R axis, we generated mice lacking Serpinf1 (PEDF) and Pnpla2 (PEDF-R). Combined loss of Serpinf1 and Pnpla2 resulted in severe retinal degeneration characterized by outer nuclear layer (ONL) thinning, outer segment (OS) shortening, reduced rhodopsin and cone opsin expression, increased TUNEL-positive nuclei, and enhanced retinal autofluorescence associated with altered lipid distribution. Lipid-associated markers, including TIP47, PLIN5, and BODIPY, exhibited abnormal distribution patterns in mutant retinas, indicating disrupted lipid storage and trafficking. Loss of PEDF/PEDF-R signaling also impaired photoreceptor-rod bipolar cell connectivity, as demonstrated by reduced PKC/synaptophysin colocalization, and resulted in diminished electroretinographic responses. Lipid Imaging mass spectrometry revealed decreases in some lipid abundances in photoreceptor outer segment and inner segment/outer nucleus layer, while lipids containing arachidonic acid and docosahexaenoic acid-containing lipids showed increased abundance. Together these findings identify the PEDF/PEDF-R signaling axis as a key regulator of retinal phospholipid homeostasis that couples lipid metabolism to photoreceptor survival and visual function.

neuroscience↗

bioRxiv2024

H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

Photoreceptor death causes blinding inheritable retinal diseases, such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances, finding effective treatments is urgent. This study focuses on developing a targeted approach by evaluating the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF), known to restrict common cell death pathways associated with retinal diseases. Peptides with affinity for the PEDF receptor, PEDF-R, (17-mer and H105A) delivered via eye drops reached the retina, efficiently promoted photoreceptor survival, and improved retinal function in RP mouse models based on both the rd10 mutation and the rhodopsin P23H mutation. Additionally, intravitreal delivery of AAV-H105A vectors delayed photoreceptor degeneration in the latter RP mouse model. Furthermore, peptide H105A specifically prevented photoreceptor death induced by oxidative stress, a contributing factor to RP progression, in human retinal organoids. This promising approach for peptide eye drop delivery holds significant potential as a therapeutic for preventing photoreceptor death in retinal disorders, offering a high safety profile, low invasiveness and multiple delivery options. One Sentence SummaryNeurotrophic PEDF peptides delivered as eye drops preserve photoreceptor viability, morphology, and function in models of human retinal diseases.

neuroscience↗

bioRxiv2021

Degradation of Photoreceptor Outer Segments by the Retinal Pigment Epithelium Requires Pigment Epithelium-derived Factor Receptor (PEDF-R)

PurposeTo examine the contribution of PEDF-R to the phagocytosis process. Previously, we identified PEDF-R, the protein encoded by the PNPLA2 gene, as a phospholipase A2 in the retinal pigment epithelium (RPE). During phagocytosis, RPE cells ingest abundant phospholipids and protein in the form of photoreceptor outer segment (POS) tips, which are then hydrolyzed. The role of PEDF-R in RPE phagocytosis is not known. MethodsMice in which PNPLA2 was conditionally knocked out in the RPE were generated (cKO). Mouse RPE/choroid explants were cultured. Human ARPE-19 cells were transfected with siPNPLA2 silencing duplexes. POS were isolated from bovine retinas. The phospholipase A2 inhibitor bromoenol lactone was used. Transmission electron microscopy, immunofluorescence, lipid labeling, pulse-chase experiments, western blots, and free fatty acid and {beta}-hydroxybutyrate assays were performed. ResultsThe RPE of the cKO mice accumulated lipids as well as more abundant and larger rhodopsin particles compared to littermate controls. Upon POS exposure, RPE explants from cKO mice released less {beta}-hydroxybutyrate compared to controls. After POS ingestion during phagocytosis, rhodopsin degradation was stalled both in cells treated with bromoenol lactone and in PNPLA2-knocked-down cells relative to their corresponding controls. Phospholipase A2 inhibition lowered {beta}-hydroxybutyrate release from phagocytic RPE cells. PNPLA2 knock down also resulted in a decline in fatty acids and {beta}-hydroxybutyrate release from phagocytic RPE cells. ConclusionsPEDF-R downregulation delayed POS digestion during phagocytosis. The findings imply that efficiency of RPE phagocytosis depends on PEDF-R, thus identifying a novel contribution of this protein to POS degradation in the RPE.

biochemistry↗

bioRxiv2021

PEDF and Derived Peptides Prevent Apoptosis and Promote Differentiation of Retinal Photoreceptors

Pigment epithelium-derived factor (PEDF) is a cytoprotective protein for the retina. We hypothesize that this protein acts on neuronal survival and differentiation of photoreceptor cells in culture. The purpose of the present study was to evaluate the neurotrophic effects of PEDF and its fragments in an in vitro model of cultured primary retinal neurons that die spontaneously in the absence of trophic factors. Results show that PEDF protected photoreceptor precursors from apoptosis, preserved mitochondrial function and promoted polarization of opsin enhancing their developmental process, as well as induced neurite outgrowth in amacrine neurons. These effects were abolished by an inhibitor of the PEDF receptor or receptor-derived peptides that block ligand/receptor interactions. While all the activities were specifically conferred by short peptide fragments (17 amino acid residues) derived from the PEDF neurotrophic domain, no effects were triggered by peptides from the PEDF antiangiogenic region. The observed effects on retinal neurons imply a specific activation of the PEDF receptor by a small neurotrophic region of PEDF. Our findings support the neurotrophic PEDF peptides as neuronal guardians for the retina, highlighting their potential as promoters of retinal differentiation, and inhibitors of retina cell death and its blinding consequences.

cell biology↗