Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity

Abstract

Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases caused by peroxisomal dysfunction. Importantly, most patients suffering from peroxisomal biogenesis disorders, even those with a milder disease course, present with a number of ocular symptoms, including retinopathy. Patients with a selective defect in either peroxisomal α- or β-oxidation or ether lipid synthesis also suffer from vision problems. In this review, we thoroughly discuss the ophthalmological pathology in peroxisomal disorder patients and, where possible, the corresponding animal models, with a special emphasis on the retina. In addition, we attempt to link the observed retinal phenotype to the underlying biochemical alterations. It appears that the retinal pathology is highly variable and the lack of histopathological descriptions in patients hampers the translation of the findings in the mouse models. Furthermore, it becomes clear that there are still large gaps in the current knowledge on the contribution of the different metabolic disturbances to the retinopathy, but branched chain fatty acid accumulation and impaired retinal PUFA homeostasis are likely important factors.

Cell Type-Selective Loss of Peroxisomal β-Oxidation Impairs Bipolar Cell but Not Photoreceptor Survival in the Retina

“…Over the years, several mouse models for peroxisomal disorders have been developed [ 58 ]. However, until now only the retinal phenotype of the Mfp2 −/− mouse and the Pex1 knockin mouse, homozygous for the most common human PEX1 mutation (G843D) ( Pex1 G844D ), have been reported [ 17 , 19 , 59 ].…”

Dysfunctional peroxisomal lipid metabolisms and their ocular manifestations

“…ACOX1 is abundantly expressed in the RPE as compared to neural retina, whereas the distribution of ACOX2 and ACOX3 in RPE and retinal layers remains unclear (Das et al, 2019). ACOX1 deficiency results in premature death in adolescence and are associated with abnormal retinal pigmentation, retinal degeneration, and optic atrophy (Das et al, 2021). Patients with ACOX1 deficiency have elevated plasma and fibroblast saturated VLCFA and comparable saturated LCFA, BCFA (phytanic acid), and DHCA/THCA to control (Ferdinandusse et al, 2007).…”

“…MFE-2 is equally or more expressed in the neural retina than RPE, whereas expressions of MFE-1 has yet to be elucidated in the eyes (Das et al, 2019). Severe MFE-2 deficiency may manifest symptoms comparable to that of PBD-ZSD; however milder juvenile onset deficiency may present with abnormal retinal pigmentation with normal visual acuity (Das et al, 2021). Patients with MFE-2 deficiency have elevated levels of saturated VLCFA, BCFA (pristanic acid), and DHCA/ THCA and reduced levels of plasma and retinal DHA (Martinez, 1992;Ferdinandusse et al, 2006a).…”

Retinopathy of prematurity: Metabolic risk factors

“…Although mitochondria are the primary organelle for fatty acid oxidation, peroxisomes uniquely oxidize very long-chain fatty acids which cannot be processed by mitochondria into shorter chains that can be used. Peroxisomal disorders are associated with retinal ganglion cell loss, and retinal degeneration ( Chen et al, 2022 ; Das et al, 2021 ). In Zellweger syndrome with mutations in PEX genes involved in peroxisomal biogenesis, there is loss of retinal cells (photoreceptors, retinal ganglion cells) and diminished ERG signals.…”

“…In Zellweger syndrome with mutations in PEX genes involved in peroxisomal biogenesis, there is loss of retinal cells (photoreceptors, retinal ganglion cells) and diminished ERG signals. Gene defects in peroxisomal α- and β-oxidation may also cause attenuated light responses, decreased visual acuity, and blindness ( Chen et al, 2022 ; Das et al, 2021 ). Although omega-3 long-chain polyunsaturated fatty acids are primarily obtained from dietary sources, there is some endogenous production from shorter-chain precursors.…”