Geographic characterization of RPE structure and lipid changes in the PEX1-p.Gly844Asp mouse model for Zellweger spectrum disorder DOI Creative Commons
Samy Omri, Catherine Argyriou, Rachel S. Pryce

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Abstract Peroxisome Biogenesis Disorders-Zellweger Spectrum (PBD-ZSD) are a heterogenous group of autosomal recessive disorders caused by defects in PEX genes whose proteins required for peroxisome assembly and function. Peroxisomes ubiquitous organelles that play critical role complex lipid metabolism. Dysfunctional peroxisomes ZSD cause multisystem effects, with progressive retinal degeneration (RD) leading to childhood blindness being one the most frequent clinical findings. Despite progress understanding normal cellular functions, much remains unknown about how their deficiency causes RD, there is no treatment. To study RD pathophysiology this disease, we used knock-in PEX1-p.GlyG844Asp (G844D) mouse model milder ZSD, which represents common human PEX1-p.Gly843Asp allele. We previously reported diminished function, functional vision, neural retina structural model. Beyond retina, pigment epithelium (RPE) have been patients murine models single enzyme deficiency, suggesting RPE may contribute overall progression disease. Here, investigate phenotype our PEX1-G844D model, observing morphological, inflammatory, changes at 1, 3, 6 months age. report cell appears 3 age worsens time, starts dorsal pole, accompanied subretinal inflammatory infiltration. match these events remodelling using imaging mass spectrometry allowed regional analysis specific layer. identified 47 alterations precede changes, 10 localized pole. 32 persist months, signature 14 new occur concurrent histological changes. Changes peroxisome-dependent lipids detected liquid chromatography tandem (reduced docosahexanoic acid increased very long chain lysophosphatidylcholines) exacerbated over time. This first characterization any animal situ peroxisome-deficient tissue. Our findings reveal candidate drivers could be targeted alleviate as well biomarkers evaluate retinopathy response therapy.

Language: Английский

The peroxisome: an update on mysteries 3.0 DOI Creative Commons

Rechal Kumar,

Markus Islinger, Harley L. Worthy

et al.

Histochemistry and Cell Biology, Journal Year: 2024, Volume and Issue: 161(2), P. 99 - 132

Published: Jan. 20, 2024

Language: Английский

Citations

20
The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment DOI Creative Commons
Steven F. Abcouwer, Bruna Miglioranza Scavuzzi, Phillip E. Kish

et al.

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: March 25, 2024

Abstract The retinal pigment epithelium (RPE) maintains photoreceptor viability and function, completes the visual cycle, forms outer blood-retinal barrier (oBRB). Loss of RPE function gives rise to several monogenic dystrophies contributes age-related macular degeneration. Retinal detachment (RD) causes separation neurosensory retina from underlying RPE, disrupting functional metabolic relationships between these layers. Although response RD is highly studied, little known about how responds loss this interaction. RNA sequencing (RNA-Seq) was used compare normal detached in C57BL6/J mouse. naïve mouse transcriptome compared previously published signature gene lists union 14 genes ( Bmp4 , Crim1 Degs1 Gja1 Itgav Mfap3l Pdpn Ptgds Rbp1 Rnf13 Rpe65 Slc4a2 Sulf1 Ttr ) representing a core set applicable across rodent human derived. Gene ontology enrichment analysis (GOEA) identified expected features functions, such as pigmentation, phagocytosis, lysosomal proteasomal degradation proteins, function. Differentially expressed (DEG) at 1 7 days post (dprd) were defined mRNA with significant (p adj ≤0.05) fold change (FC) 0.67 ≥ FC 1.5 versus RPE. exhibited dramatic changes dprd, 2297 DEG identified. KEGG pathways biological process GO groups related innate immune responses significantly enriched. Lipocalin 2 Lcn2 chemokines upregulated, while numerous synthesis, tight junctions downregulated dprd. largely transient, only 18 including upregulation complement C4b . Validation studies confirmed RNA-Seq results. Thus, quickly downregulates cell-specific functions mounts an defense following RD. Our data demonstrate that inflammatory may play role attraction cells subretinal space.

Language: Английский

Citations

5
Mitochondrial DNA Damage in the Retinal Pigmented Epithelium (RPE) and Its Role in RPE Pathobiology DOI
Raela B Ridley,

Ashley Amontree,

Alfred S. Lewin

et al.

Advances in experimental medicine and biology, Journal Year: 2025, Volume and Issue: unknown, P. 375 - 379

Published: Jan. 1, 2025

Language: Английский

Citations

0
Nutrient supplementation mitigates retinal dysfunction in Acox1 knockout mice with impaired peroxisomal fatty acid oxidation DOI Creative Commons
Myriam Boeck, Hitomi Yagi, Chuck T. Chen

et al.

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Dyslipidemia contributes to many retinal diseases, but underlying lipid processing pathways are not fully understood. Peroxisomes oxidize very long-chain fatty acids and generate docosahexaenoic acid (DHA). Mutations in peroxisomal genes can result severe neural dysfunction. However, therapeutic approaches for diseases remain scarce, dietary strategies yield inconsistent results. This study sought elucidate metabolic adaptations resulting from impaired oxidation evaluate the potential of nutrient supplementation disease. In mice with global knockout (KO) acyl-coenzyme A oxidase 1 (Acox1), encoding first rate-limiting enzyme oxidation, retina was characterized at postnatal day (P) 30 during development. Retinal thickness, photoreceptor structure, function were examined. Proteome analysis utilized molecular mechanistic investigation. Metabolomics profiling conducted alterations retina. Nutrient intervention performed test if providing deficient nutrients could attenuate observed P30 Acox1 KO mice, we signaling, accompanied by reduced expression involved phototransduction. Proteomics suggested diminished glucose mitochondrial metabolism, supported decreased number DNA copy number. showed abundance pyruvate, pyruvate P30-P60 attenuated dysfunction P60. Furthermore, exhibited a significant decrease omega-3 (n-3) compensatory increase n-6 acids. Dietary DHA or plus arachidonic (n-6) mitigated progression mice. dysfunction, number, imbalance oxidation. may offer promising approach diseases.

Language: Английский

Citations

0
Spatial characterization of RPE structure and lipids in the PEX1-p.Gly844Asp mouse model for Zellweger spectrum disorder DOI Creative Commons
Samy Omri, Catherine Argyriou, Rachel S. Pryce

et al.

Journal of Lipid Research, Journal Year: 2025, Volume and Issue: unknown, P. 100771 - 100771

Published: March 1, 2025

Zellweger Spectrum Disorder (ZSD) is caused by defects in PEX genes, whose proteins are required for peroxisome assembly and function. Peroxisome dysfunction ZSD causes multisystem effects, with progressive retinal degeneration (RD) among the most frequent clinical findings. However, much remains unknown about how deficiency RD. To study RD pathophysiology ZSD, we used PEX1-p.Gly844Asp (G844D) mouse model, which represents common human PEX1-p.Gly843Asp allele. We previously reported diminished function, functional vision, neural retina structural this model. Here, investigate pigment epithelium (RPE) phenotype, examining morphological, inflammatory, lipid changes at 1, 3, 6 months of age. report that RPE cells exhibit evident 3 worsens time, starts dorsal pole, accompanied subretinal inflammatory cell infiltration. match these events imaging mass spectrometry regional analysis lipids RPE. identified 47 alterations preceding changes, 9 localize to pole. 29 persist months, remodeling pole signature. 13 new occur concurrent histological changes. Abnormalities peroxisome-dependent detected LC/MS/MS exacerbated over time. This first characterization a situ peroxisome-deficient tissue. Our findings uncover potential drivers progression identify candidate biomarkers retinopathy response therapy.

Language: Английский

Citations

0
Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease DOI Creative Commons
Michael Landowski,

Purnima Gogoi,

Sakae Ikeda

et al.

Frontiers in Ophthalmology, Journal Year: 2024, Volume and Issue: 4

Published: Jan. 31, 2024

Aging is the most significant risk factor for age-related diseases in general, which true eye including macular degeneration (AMD). Therefore, order to identify potential therapeutic targets these diseases, it crucial understand normal aging process and how its mis-regulation could cause at molecular level. Recently, abnormal lipid metabolism has emerged as one major aspect of symptoms retina. Animal models provide excellent means study factors that regulate relation symptoms. Central this review role transmembrane protein 135 (TMEM135) TMEM135 was identified through characterization a mutant mouse strain exhibiting accelerated retinal positional cloning responsible mutation within gene, indicating regulating Over past decade, functions have been explored various tissues, providing insights into regulation metabolism, particularly action multiple organelles. Studies indicated regulator peroxisomes, mitochondria, their interaction. Here, we an overview lipids. The also discusses age-dependent phenotypes mice with perturbations, emphasizing importance balanced function health retina other tissues heart, liver, adipose tissue. Finally, explore roles human connecting pathobiology AMD.

Language: Английский

Citations

3
Benefits and Caveats in the Use of Retinal Pigment Epithelium-Specific Cre Mice DOI Open Access
Sai Kocherlakota, Myriam Baes

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1293 - 1293

Published: Jan. 20, 2024

The retinal pigment epithelium (RPE) is an important monolayer of cells present in the outer retina, forming a major part blood-retina barrier (BRB). It performs many tasks essential for maintenance integrity and function. With increasing knowledge it becoming clear that both common disorders, like age-related macular degeneration, rare genetic disorders originate RPE. This calls better understanding functions various proteins within In this regard, mice enabling RPE-specific gene deletion are powerful tool to study role particular protein RPE their native environment, simultaneously negating any potential influences systemic changes. Moreover, since interact closely with adjacent photoreceptors, these also provide excellent avenue importance function retina as whole. review, we outline compare features Cre created purpose, which allow inducible or non-inducible knockout interest. We summarize benefits caveats involved use such mouse lines, allowing researchers make well-informed decision on choice relation research needs.

Language: Английский

Citations

2
Syndromic Retinitis Pigmentosa DOI Creative Commons
Jessica S. Karuntu,

Hind Almushattat,

Xuan‐Thanh‐An Nguyen

et al.

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: unknown, P. 101324 - 101324

Published: Dec. 1, 2024

Language: Английский

Citations

1
DHA Shortage Causes the Early Degeneration of Photoreceptors and RPE in Mice With Peroxisomal β-Oxidation Deficiency DOI Creative Commons
Daniëlle Swinkels, Sai Kocherlakota,

Yannick Das

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2023, Volume and Issue: 64(14), P. 10 - 10

Published: Nov. 7, 2023

Patients deficient in peroxisomal β-oxidation, which is essential for the synthesis of docosahexaenoic acid (DHA, C22:6n-3) and breakdown very-long-chain polyunsaturated fatty acids (VLC-PUFAs), both important components photoreceptor outer segments, develop retinopathy present with retinopathy. The representative mouse model lacking central enzyme this pathway, multifunctional protein 2 (Mfp2-/-), also show early-onset retinal decay cell-autonomous pigment epithelium (RPE) degeneration, accompanied by reduced plasma DHA levels. In study, we investigated whether supplementation can rescue degeneration Mfp2-/- mice.Mfp2+/- breeding pairs their offspring were fed a 0.12% or control diet during gestation lactation until sacrifice. Offspring analyzed function via electroretinograms lipid composition neural retina lipidome analysis gas chromatography, respectively, histologically using sections RPE flatmounts at ages 4, 8, 16 weeks.DHA to mice restored levels prevented shortening, death, impaired functioning 8 weeks. addition, temporarily improved ability phagocytose segments delayed dedifferentiation. However, despite initial integrity, could not prevent weeks.We reveal that shortage systemic supply pivotal early mice. Furthermore, report adequate are only photoreceptors but homeostasis.

Language: Английский

Citations

3
Retinoid Synthesis Regulation by Retinal Cells in Health and Disease DOI Creative Commons
Massimiliano Andreazzoli, Biancamaria Longoni, Debora Angeloni

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(10), P. 871 - 871

Published: May 18, 2024

Vision starts in retinal photoreceptors when specialized proteins (opsins) sense photons via their covalently bonded vitamin A derivative 11cis retinaldehyde (11cis-RAL). The reaction of non-enzymatic aldehydes with amino groups lacks specificity, and the products may trigger cell damage. However, reduced synthesis 11cis-RAL results photoreceptor demise suggests need for careful control over handling by cells. This perspective focuses on retinoid(s) synthesis, adult retina, role during retina development. It also explores potential importance 9cis derivatives regulating retinoid impact development survival. Additionally, recent advancements suggesting pivotal nature regulation cone viability are discussed.

Language: Английский

Citations

0