Biology subjects

Becker-Pauly, C.

Publications and source records attributed to Becker-Pauly, C..

3 recordsLinked to original sources

bioRxiv2025

Pathological meprin α expression associated with degradation of dermokine drives a psoriasis-like skin phenotype in a genetic mouse model

Keratinocyte proliferation and differentiation is regulated via proteolytic networks. Dysregulation of proteases within these networks can cause hyperproliferative and inflammatory skin disorders. In healthy skin the metalloprotease meprin is localized in the stratum basale. In contrast, in wound healing tissue and psoriatic lesions increased meprin levels are found in the upper epidermal layers. We developed a transgenic mouse model for inducible expression of pathological meprin levels (K5M) to investigate its epidermal degradome and identify molecular links to keratinocyte proliferation and skin inflammation. K5M mice developed a severe skin phenotype characterized by hyperkeratosis, acanthosis and parakeratosis accompanied by increased transepidermal water loss and a strong inflammatory response within six days after induction of meprin overexpression. Histological and molecular analyses showed that increasing meprin expression correlates with meprin activity and keratinocyte hyperproliferation. Proteomics analyses revealed massive changes in proteins associated with keratinocyte differentiation and epidermal barrier integrity already three days after induction. N-terminomics data indicated a dominant chymotryptic activity with elevated proteolytic turnover of proteins associated with the cytoskeleton, cellular stress responses and cell adhesion. By filtering for cleavage sites that match with the specificity of meprin , we identified highly elevated dermokine-derived peptides. Subsequent mass spectrometric analyses validated dermokine as a novel substrate of meprin and identified the cleavage site, which is highly conserved in mammals. Based on the striking similarities with the phenotype reported for dermokine {beta}{gamma}-/- mice, we propose meprin as a central regulator of keratinocyte proliferation and leukocyte recruitment by proteolytic inactivation of dermokine. Hence, pathological meprin activity could be a driver of hyperproliferative, inflammatory skin disorders like psoriasis vulgaris.

molecular biology↗

bioRxiv2023

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases

Proteolytic cell surface release ( shedding) of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated for the human body thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimers disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregates of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.

neuroscience↗

bioRxiv2019

The Alzheimer’s disease associated bacterial protease RgpB from P. gingivalis activates the alternative β-secretase meprin β thereby increasing Aβ generation

Alzheimers disease (AD) is the most common type of dementia and characterized by tau hyperphosphorylation, oxidative stress, reactive microglia and amyloid-{beta} (A{beta}) deposits. A recent study revealed that Porphyromonas gingivalis infection is associated with amyloid {beta} generation in Alzheimers disease. Increased A{beta} levels, tau degradation and neuronal toxicity were observed as a consequence of ginigipain R (RgpB) activity, a cysteine protease constitutively secreted by P. gingivalis. Of note, we previously identified RgpB as a potent activator of the metalloproteinase meprin {beta}. Interestingly, meprin {beta} is an alternative {beta}-secretase of the amyloid precursor protein (APP), which together with the {gamma}-secretase leads to the generation of aggregation-prone N-terminally truncated A{beta}2-x peptides. Importantly, identification of a risk gene variant of meprin {beta} (rs173032) for Alzheimers disease using whole-exome sequencing of the BDR cohort further supports the impact of this alternative {beta}-secretase. Thus, we wondered if increased A{beta} levels as a consequence of P. gingivalis colonization into the brain might be due to meprin {beta} activation by RgpB. Here, we demonstrate that i) upon incubation with RgpB the proteolytic activity of meprin {beta} at the cell surface of transfected HEK cells or of endogenously expressed enzyme in SH-SY5Y neuroblastoma cells was significantly increased, and that ii) RgpB-mediated increase in meprin {beta} activity leads to massive generation of A{beta}-peptides. In conclusion, our findings would further explain the pathogenesis of P. gingivalis in AD brain.

neuroscience↗