Biology subjects

Van Veldhoven, P. P.

Publications and source records attributed to Van Veldhoven, P. P..

3 recordsLinked to original sources

bioRxiv2023

DHA shortage causes the early degeneration of photoreceptors and RPE in mice with peroxisomal β-oxidation deficiency

PurposePatients deficient in peroxisomal {beta}-oxidation, which is essential for the synthesis of docosahexaenoic acid (DHA, C22:6n-3) and breakdown of very long-chain polyunsaturated fatty acids (VLC-PUFAs), both important components of photoreceptor outer segments, present with retinopathy. The representative mouse model lacking the central enzyme of this pathway, multifunctional protein 2 (Mfp2-/-), also develops early onset retinal decay and cell-autonomous retinal pigment epithelium (RPE) degeneration, accompanied by reduced plasma and retinal DHA levels. In this study, we investigated whether DHA supplementation can rescue the retinal degeneration of Mfp2-/- mice. MethodsMfp2+/- breeding pairs and their offspring were fed a 0.12% DHA or control diet during gestation, lactation and until sacrifice. Offspring were analysed for retinal function via electroretinograms, for lipid composition of neural retina and plasma with lipidome analysis and gas chromatography respectively, and histologically using retinal sections and RPE flatmounts at the age of 4, 8 and 16 weeks. ResultsDHA supplementation to Mfp2-/- mice restored retinal DHA levels and prevented photoreceptor shortening, impaired functioning and death until 8 weeks. In addition, rescue of retinal DHA levels temporarily improved the ability of the RPE to phagocytose outer segments and delayed the RPE dedifferentiation. However, despite the initial rescue of retinal integrity, DHA supplementation could not prevent retinal degeneration at 16 weeks. ConclusionsWe reveal that the shortage of systemic supply of DHA is pivotal for the early retinal degeneration in Mfp2-/- mice. Furthermore, we unveil that adequate retinal DHA levels are essential for both photoreceptor and RPE homeostasis.

cell biology↗

bioRxiv2021

Peroxisome-derived hydrogen peroxide can modulate the sulfenylation profiles of key redox signaling proteins

Ever since the first characterization of peroxisomes, a central theme has been their involvement in cellular hydrogen peroxide (H2O2) metabolism. While the reputation of H2O2 drastically changed from an exclusively toxic molecule to a signaling messenger, the regulatory role of peroxisomes in these signaling events is still largely underappreciated. This is mainly because the number of known protein targets of peroxisome-derived H2O2 is rather limited and testing of specific targets is predominantly based on knowledge previously gathered in related fields of research. To gain a broader and more systematic insight into the role of peroxisomes in redox signaling, an unbiased approach is urgently needed. To accomplish this goal, we have combined a previously developed cell system in which peroxisomal H2O2 production can be modulated with a yeast AP-1-like-based sulfenome mining strategy to inventory protein thiol targets of peroxisome-derived H2O2 in different subcellular compartments. Using this unbiased approach, we were able to identify specific and common targets of peroxisome-derived and exogenous H2O2 in peroxisomes, the cytosol, and mitochondria. We also observed that the sulfenylation kinetics profiles of key targets belonging to different protein families can vary considerably. In addition, we obtained compelling but indirect evidence that peroxisome-derived H2O2 may oxidize at least some of its targets through a redox relay mechanism. In conclusion, given that sulfenic acids function as key intermediates in H2O2 signaling, the findings presented in this study provide initial but critical insight into how peroxisomes may be integrated in the cellular H2O2 signaling network. HighlightsO_LIYAP1C-trapping is a robust tool to assess the peroxisomal H2O2-dependent sulfenome C_LIO_LIExogenous and peroxisome-derived H2O2 have both common and distinct targets C_LIO_LIANXA2, PRDX1, and SKP1 are major targets of peroxisome-derived H2O2 C_LIO_LIThe sulfenylation kinetics profiles of key redox-active proteins vary considerably C_LIO_LIProduction of H2O2 inside peroxisomes directly impacts the mitochondrial sulfenome C_LI

cell biology↗

bioRxiv2018

Astrocytes integrate local sensory and brain-wide neuromodulatory signals.

Astrocytes play multiple functions in the central nervous system, from control of blood flow through to modulation of synaptic activity. Transient increases in intracellular Ca2+ are thought to control these activities. The prevailing concept is that these Ca2+ transients are triggered by distinct pathways, with little mechanistic and functional overlap. Here we demonstrate that astrocytes in visual cortex of mice encode local visual signals in conjunction with arousal state, functioning as multi-modal integrators. Such activity adds an additional layer of complexity to astrocyte function and may enable astrocytes to specifically and subtly regulate local network activity and plasticity.

neuroscience↗