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Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1007\/s00018-025-05971-8","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:42:19Z","timestamp":1764578539000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency"],"prefix":"10.1007","volume":"83","author":[{"given":"Julia","family":"Merz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warda","family":"Darwisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Fairless","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Vorwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharau","family":"Darwisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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