Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency

Sep 30, 2026

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Patients deficient in the peroxisomal membrane protein ACBD5 develop retinal dystrophy and progressive decline in visual acuity, yet the underlying retinodystrophy mechanism remains insufficiently defined. An ACBD5-deficient mouse model was assessed using immunofluorescence microscopy, electron microscopy, full-field electroretinography, and analytical/spatial mass spectrometry lipidomics. Results indicate moderate degeneration across multiple retinal cell types with strong astroglial and microglial activation.

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Abstract

Introduction

Cellular and Molecular Life Sciences (2026) 83:26 [https://doi.org/10.1007/s00018-025-05971-8](https://doi.org/10.1007/s00018-025-05971-8) Cellular and Molecular Life Sciences ORIGINAL ARTICLE Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency Julia Merz1,2 · Elisabeth Müller3,4 · Warda Darwisch1,2 · Richard Fairless5,6 · Yixin Wang7 · Silke Vorwald1,2 · Sharau Darwisch1,2 · E. Ronald Curticean8 · Feng Shao7 · Irene Wacker8 · Rasmus R. Schröder8 · Claudia Pitzer9 · Christian Schultz1,2 · Jan-Bert van Klinken10,11,12 · Frederic M. Vaz10,12,13 · Frank Kratzer14 · Kathrin Schwarz14 · Jürgen G. Okun14 · Yuxi Feng7 · Carsten Hopf2,3,4 · Markus Islinger1,2,15 Received: 16 April 2025 / Revised: 5 October 2025 / Accepted: 22 October 2025 © The Author(s) 2025 Abstract Patients deficient in the peroxisomal membrane protein ACBD5 regularly exhibit a dystrophy of the retina along with decline in visual acuity. Despite the prevalent retinal phenotype, information on the pathogenesis of the retinodystrophy is limited. To gain insight into the cellular, subcellular and molecular alterations occurring in the retina, we analyzed an ACBD5-deficient mouse model by immunofluorescence microscopy, electron microscopy, full-field electroretinography (ffERG) and as well as analytical and spatial mass spectrometry (MS)-based lipidomics techniques. Histological results implied that ACBD5-deficient mice exhibit a moderate degeneration of photoreceptor, bipolar, ganglion and retinal pigment epithelial cells accompanied, however, by a prominent activation of astroglia and microglia. Reduced a-and b-wave amplitudes from ffERG point to a severe functional dysregulation of retinal signal transduction with a focus at the level of the information-processing cell of the inner retina. At the lipidome level, very long-chain polyunsaturated fatty acids (VLC-PUFA) accumulated in phosphatidylcholines from retina homogenates, most likely disrupted by a decline in peroxisome functions. Remarkably, as revealed by MALDI MS imaging, these lipidome changes affected neither the whole retina nor the photoreceptor outer segments (POS), where VLC-PUFAs display the highest concentration in phospholipids of POS membrane discs. In contrast, VLC-PUFAs in ACBD5-deficient mice consistently accumulated in the inner retinal region from the outer (OPL) to inner plexiform layer (IPL) . In line with VLC-PUFA-accumulations, photoreceptor ribbon synapses in the OPL showed morphological signs of degeneration on the ultrastructural level. Hence, peroxisomal dysfunction appears to affect cell type-specific lipid homeostasis, thereby disrupting local retinal membrane physiology leading to a severe neuroinflammation of the ACBD5-deficient mouse retina. Keywords Peroxisomes · Metabolic disorders · Retinodystrophy · Very long-chain fatty acids (VLCFA) · RDLKD (ACBD5-deficiency) Introduction Peroxisomes are ubiquitous, small, membrane-bound and mostly spherical organelles [1] . Functionally, they contribute to several pathways of lipid metabolism such as the degradation of very long-chain and branched-chain fatty acids as well as the synthesis of ether lipids and distinct ω6-and ω3-polyunsaturated fatty acids such as docosahexaenoic Extended author information available on the last page of the article acid (DHA) [2]. Moreover, they are involved in the defense against reactive oxygen species (ROS), viruses and the mediation of inflammatory responses. Inherited disorders of peroxisomal metabolism and biogenesis are generally characterized by severe degenerative alterations in the central nervous system [3] . Since the optic part of the eye differentiates from a vesicular outgrowth of the brain and exhibits a highly specialized membrane lipidome, even milder 1 3 forms of peroxisomal disorders often present with a retinal pathology [4] . However, unlike for patients from the

FAQs

What does the study aim to clarify about ACBD5-related retinal disease?

It investigates cellular, subcellular, and molecular alterations in the retina caused by ACBD5 deficiency to explain the pathogenesis of retinodystrophy.

How was the ACBD5-deficient mouse model evaluated?

Through immunofluorescence microscopy, electron microscopy, full-field electroretinography, and analytical plus spatial mass spectrometry lipidomics.

What key lipidomic finding links ACBD5 deficiency to retinal dysfunction?

Very long-chain polyunsaturated fatty acids accumulate in phosphatidylcholines, with MALDI MS imaging showing consistent localization from the outer plexiform layer toward inner plexiform layers.

Sep 30, 2026

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