Copper-amyloid-β ROS production: Copper ions (red sphere, see picture) have been found to accumulate in amyloid-β plaques and play a role in the generation of reactive oxygen species (ROS) within this context. Mass spectrometry studies were able to detail the sites of oxidation damage and shed new light on the mechanism of ROS production, important for the understanding of the pathogenicity of amyloid-β peptides.
Kupferionen (rote Kugel im Bild) akkumulieren in Amyloid‐β‐Plaques und spielen dort eine Rolle bei der Erzeugung reaktiver Sauerstoffspezies (ROS). Massenspektrometrische Studien zeigen, an welchen Stellen eine oxidative Schädigung auftritt, was neue Einblicke in den Mechanismus der ROS‐Produktion bietet und dadurch zum besseren Verständnis der Pathogenität von Amyloid‐β‐Peptiden beiträgt.
Plant cells are surrounded by cell walls playing many roles during development and in response to environmental constraints. Cell walls are mainly composed of polysaccharides (cellulose, hemicelluloses and pectins), but they also contain proteins which are critical players in cell wall remodeling processes. Today, the cell wall proteome of Arabidopsis thaliana, a major dicot model plant, comprises more than 700 proteins predicted to be secreted (cell wall proteins-CWPs) identified in different organs or in cell suspension cultures. However, the cell wall proteome of rosettes is poorly represented with only 148 CWPs identified after extraction by vacuum infiltration. This new study allows enlarging its coverage. A destructive method starting with the purification of cell walls has been performed and two experiments have been compared. They differ by the presence/absence of protein separation by a short 1D-electrophoresis run prior to tryptic digestion and different gradient programs for peptide separation before mass spectrometry analysis. Altogether, the rosette cell wall proteome has been significantly enlarged to 361 CWPs, among which 213 newly identified in rosettes and 57 newly described. The identified CWPs fall in four major functional classes: 26.1% proteins acting on polysaccharides, 11.1% oxido-reductases, 14.7% proteases and 11.7% proteins possibly related to lipid metabolism.
Cell wall proteins (CWPs) play critical and dynamic roles in plant cell walls by contributing to developmental processes and response to environmental cues. Since the CWPs go through the secretion pathway, most of them undergo post-translational modifications (PTMs) which can modify their biological activity. Glycosylation is one of the major PTMs of CWPs and refers to N-glycosylation, O-glycosylation and glypiation. Each of these PTMs occurs in different amino acid contexts which are not all well defined. This article deals with the hydroxylation of Pro residues which is a prerequisite for O-glycosylation of CWPs on hydroxyproline (Hyp) residues. The location of Hyp residues is well described in several structural CWPs, but yet rarely described in other CWPs. In this article, it is studied in detail in five Arabidopsis thaliana proteins using mass spectrometry data: one of them (At4g38770, AtPRP4) is a structural CWP containing 32.5% of Pro residues arranged in typical motifs, the others are either rich (27–28%, At1g31580 and At2g10940) or poor (6–8%, At1g09750 and At3g08030) in Pro residues. The known rules of Pro hydroxylation allowed a good prediction of Hyp location in AtPRP4. However, they could not be applied to the other proteins whatever their Pro content. In addition, variability of the Pro hydroxylation patterns was observed within some amino acid motifs in all the proteins and new patterns of Pro hydroxylation are described. Altogether, this work shows that Hyp residues are present in more protein families than initially described, and that Pro hydroxylation patterns could be different in each of them. This work paves the way for completing the existing Pro hydroxylation code.
Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. In rodent, the bulk of its expression occurs in the central nervous system. Despite this, ApoD has profound effects in peripheral tissues, indicating that neural ApoD may reach peripheral organs. We endeavor to determine if cerebral ApoD can reach the circulation and accumulate in peripheral tissues. Three hours was necessary for over 40% of all the radiolabeled human ApoD (hApoD), injected bilaterally, to exit the central nervous system (CNS). Once in circulation, hApoD accumulates mostly in the kidneys/urine, liver, and muscles. Accumulation specificity of hApoD in these tissues was strongly correlated with the expression of lowly glycosylated basigin (BSG, CD147). hApoD was observed to pass through bEnd.3 blood brain barrier endothelial cells monolayers. However, cyclophilin A did not impact hApoD internalization rates in bEnd.3, indicating that ApoD exit from the brain is either independent of BSG or relies on additional cell types. Overall, our data showed that ApoD can quickly and efficiently exit the CNS and reach the liver and kidneys/urine, organs linked to the recycling and excretion of lipids and toxins. This indicated that cerebral overexpression during neurodegenerative episodes may serve to evacuate neurotoxic ApoD ligands from the CNS.
Drug nanocarriers (NCs) capable of crossing the vascular
endothelium
and deeply penetrating into dense tissues of the CNS could potentially
transform the management of neurological diseases. In the present
study, we investigated the interaction of bottle-brush (BB) polymers
with different biological barriers in vitro and in vivo and compared it to nanospheres of similar composition. In vitro internalization and permeability assays revealed
that BB polymers are not internalized by brain-associated cell lines
and translocate much faster across a blood–brain barrier model
compared to nanospheres of similar hydrodynamic diameter. These observations
performed under static, no-flow conditions were complemented by dynamic
assays performed in microvessel arrays on chip and confirmed that
BB polymers can escape the vasculature compartment via a paracellular
route. BB polymers injected in mice and zebrafish larvae exhibit higher
penetration in brain tissues and faster extravasation of microvessels
located in the brain compared to nanospheres of similar sizes. The
superior diffusivity of BBs in extracellular matrix-like gels combined
with their ability to efficiently cross endothelial barriers via a
paracellular route position them as promising drug carriers to translocate
across the blood–brain barrier and penetrate dense tissue such
as the brain, two unmet challenges and ultimate frontiers in nanomedicine.
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