A longitudinal study of retinopathy in the PEX1-Gly844Asp mouse model for mild Zellweger Spectrum Disorder. (September 2019)

• Record Type: Journal Article
• Authors: Argyriou, Catherine; Polosa, Anna; Cecyre, Bruno; Hsieh, Monica; Di Pietro, Erminia; Cui, Wei; Bouchard, Jean-François; Lachapelle, Pierre; Braverman, Nancy
• Is Part Of: Experimental eye research. Volume 186(2019)
• Publication Date: 2019-09
• Subjects: Peroxisome disorders -- Zellweger spectrum disorder -- PEX1 -- Pex1 mouse model -- Retinal degeneration; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2019.107713
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Zellweger Spectrum Disorder (ZSD) is an autosomal recessive disease caused by mutations in any one of 13 PEX genes whose protein products are required for peroxisome assembly. Retinopathy leading to blindness is one of the major untreatable handicaps faced by patients with ZSD but is not well characterized, and the requirement for peroxisomes in retinal health is unknown. To address this, we examined the progression of retinopathy from 2 to 32 weeks of age in our murine model for the common human PEX1-p.Gly843Asp allele (PEX1-p.Gly844Asp) using electrophysiology, histology, immunohistochemistry, electron microscopy, biochemistry, and visual function tests. We found that retinopathy in male and female PEX1-G844D mice was marked by an attenuated cone function and abnormal cone morphology early in life, with gradually decreasing rod function. Structural defects at the inner retina occurred later in the form of bipolar cell degradation (between 13 and 32 weeks). Inner segment disorganization and enlarged mitochondria were seen at 32 weeks, while other inner retinal cells appeared preserved. Visual acuity was diminished by 11 weeks of age, while signal transmission from the retina to the brain was relatively intact from 7 to 32 weeks of age. Molecular analyses showed that PEX1-G844D is a subfunctional but stable protein, contrary to human PEX1-G843D. Finally, C26:0 lysophosphatidylcholine was elevated in the PEX1-G844D retina, while phopshoethanolamine plasmalogen lipids were present at normal levels. These characterization studies identify therapeutic endpoints for future preclinical trials, including improving or preserving the electroretinogram response, improving visual acuity, and/or preventing loss of bipolar cells. Highlights: Cone electrophysiological function is affected earlier and more severely than rod function. B-waves are more affected than a-waves, with oscillatory potentials relatively preserved. Major structural defects are cone and inner segment disorganization and bipolar cell dropout. The PEX1-G844D mouse missense protein is stable but subfunctional. Very long chain fatty acids are elevated, while total plasmalogens are at normal levels in retina.