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000306684 1001_ $$aMerz, Julia$$b0
000306684 245__ $$aLocal accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency.
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000306684 520__ $$aPatients 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.
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000306684 650_7 $$2Other$$aMetabolic disorders
000306684 650_7 $$2Other$$aPeroxisomes
000306684 650_7 $$2Other$$aRDLKD (ACBD5-deficiency)
000306684 650_7 $$2Other$$aRetinodystrophy
000306684 650_7 $$2Other$$aVery long-chain fatty acids (VLCFA)
000306684 7001_ $$aMüller, Elisabeth$$b1
000306684 7001_ $$aDarwisch, Warda$$b2
000306684 7001_ $$0P:(DE-He78)4975d10b7009d8b29e133e7ce58e9949$$aFairless, Richard$$b3$$udkfz
000306684 7001_ $$aWang, Yixin$$b4
000306684 7001_ $$aVorwald, Silke$$b5
000306684 7001_ $$aDarwisch, Sharau$$b6
000306684 7001_ $$aCurticean, E Ronald$$b7
000306684 7001_ $$aShao, Feng$$b8
000306684 7001_ $$aWacker, Irene$$b9
000306684 7001_ $$aSchröder, Rasmus R$$b10
000306684 7001_ $$aPitzer, Claudia$$b11
000306684 7001_ $$aSchultz, Christian$$b12
000306684 7001_ $$avan Klinken, Jan-Bert$$b13
000306684 7001_ $$aVaz, Frederic M$$b14
000306684 7001_ $$aKratzer, Frank$$b15
000306684 7001_ $$aSchwarz, Kathrin$$b16
000306684 7001_ $$aOkun, Jürgen G$$b17
000306684 7001_ $$aFeng, Yuxi$$b18
000306684 7001_ $$aHopf, Carsten$$b19
000306684 7001_ $$00000-0001-8881-0902$$aIslinger, Markus$$b20
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