bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 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.

Язык: Английский