Biology subjects

Kugelmann, D.

Publications and source records attributed to Kugelmann, D..

4 recordsLinked to original sources

bioRxiv2024

Evaluation of near-infrared light therapy for the treatment of neurodegenerative diseases: Limited penetration depth into the brain likely hinders efficacy

BackgroundNear-infrared (NIR) light therapy is used to treat various musculoskeletal disorders. It has been proposed that transcranial NIR light treatment may also be beneficial for Alzheimers disease (AD). However, the ability of NIR light to penetrate the scalp and skull efficiently and induce cytoprotective responses in the brain parenchyma has not been sufficiently examined so far. This study aimed to evaluate whether the amount of NIR light that can penetrate through the human skull can cause a biological effect. MethodsThree commercially available devices (a medical laser emitting light at a wavelength of 905 nm and two LED helmets operating at wavelengths of 810 nm and 1070 nm, respectively) were used to measure the NIR light transmittance through human post-mortem skulls with a thermal power sensor. Furthermore, the biological effects of the fraction of light power that passed through the skull were investigated in a human neuronal cell line and in C. elegans. ResultsThe 905 nm laser achieved transmittances of up to 0.31% (173 {micro}W/cm2) of its input power, and the LED helmets 0.71% (41 {micro}W/cm2; 810 nm) and 0.45% (19 {micro}W/cm2; 1070 nm) of their respective input powers. NIR light exposure at a power density of 134 mW/cm2 was sufficient to activate mitochondrial metabolism in cultured human neurons and C. elegans, as demonstrated by increased cytochrome c oxidase activity and induction of mitochondrial chaperones. However, this stimulatory effect was no longer observed when the applied power density was reduced to 2.5 mW/cm2. ConclusionsMore than 99% of the NIR light emitted by the investigated devices was either absorbed or scattered by the human skull. The residual NIR light that would reach underlying brain structures was too weak to elicit biological effects. In conclusion, NIR light treatment is unlikely to be effective to treat brain diseases such as AD due to the low penetrability of the skull.

neuroscience↗

bioRxiv2024

Dsg2 truncation causes a lethal barrier breakdown in mice

Inflammatory bowel diseases (IBD) such as Crohns disease (CD) have a complex aetiology with alterations of both the intestinal epithelial barrier and the IL23/IL17 immune response. Here, we investigated the role of a novel mutation in the desmosomal cadherin desmoglein 2 gene (DSG2) in the pathogenesis of IBD. DSG2 is known to regulate intestinal epithelial barrier integrity. Genetic analysis of a CD patient revealed a novel likely pathogenic DSG2 mutation leading to a truncated protein lacking part of the intracellular domain. We generated an enterocyte-specific mouse model, recapitulating the human mutation to study how the cytoplasmic truncation of Dsg2 affects intestinal barrier properties systemically. Moreover, we analysed the intestinal genetic profile in these mice and compared it to IBD patients. We describe a first CD patient with a rare mutation in the DSG2 gene causing cytoplasmic truncation with affects Dsg2 mobility. Mice with enterocyte-specific Dsg2 truncation suffered from a lethal intestinal barrier defect and presented a skewed IL17 response similar to CD patients. We identified the desmosomal cadherin Dsg2 as a regulator of the skewed IL17 response. These data indicate that desmosomes regulate inflammation similar to psoriasis which explains why the same novel immune therapies are effective for both diseases.

cell biology↗

bioRxiv2023

Catalytic antibodies in arrhythmogenic cardiomyopathy patients cleave desmoglein 2 and N-cadherin and impair cardiomyocyte cohesion

AimsArrhythmogenic cardiomyopathy (AC) is a severe heart disease predisposing to ventricular arrhythmias and sudden cardiac death caused by mutations affecting intercalated disc (ICD) proteins and aggravated by physical exercise. Recently, autoantibodies targeting ICD proteins, including the desmosomal cadherin desmoglein 2 (DSG2), were reported in AC patients and were considered relevant for disease development and progression, particularly in patients without underlying pathogenic mutations. However, it is unclear at present whether these autoantibodies are pathogenic and by which mechanisms show specificity for DSG2 and thus can be used as a diagnostic tool. Methods and ResultsIgG fractions were purified from 15 AC patients and 4 healthy controls. Immunostainings dissociation assays, atomic force microscopy (AFM), western blot analysis and Triton-X-100 assays were performed utilizing human heart left ventricle tissue, HL-1 cells, and murine cardiac slices. Immunostainings revealed that autoantibodies against ICD proteins are prevalent in AC and most autoantibody fractions have catalytic properties and cleave the ICD adhesion molecules DSG2 and N-cadherin, thereby reducing cadherin interactions as revealed by AFM. Furthermore, most of the AC-IgG fractions causing loss of cardiomyocyte cohesion activated p38MAPK, which is known to contribute to a loss of desmosomal adhesion in different cell types, including cardiomyocytes. In addition, p38MAPK inhibition rescued the loss of cardiomyocyte cohesion induced by AC-IgGs. ConclusionOur study demonstrates that catalytic autoantibodies play a pathogenic role by cleaving ICD cadherins and thereby reducing cardiomyocyte cohesion by a mechanism involving p38MAPK activation. Finally, we conclude that DSG2 cleavage by autoantibodies could be used as a diagnostic tool for AC.

cell biology↗

bioRxiv2022

Apremilast prevents blistering in human epidermis by stabilization of keratinocyte adhesion in pemphigus.

Pemphigus vulgaris (PV) is a life-threatening blistering skin disease caused by autoantibodies (PV-IgG) destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used e.g. in psoriasis, prevents blistering in PV. Apremilast abrogated PV-IgG-induced loss of keratinocyte cohesion in ex-vivo epidermis and in vitro. This was paralleled by inhibition of keratin retraction and desmosome splitting but affected neither desmoglein (Dsg) depletion nor Dsg3 binding properties. Apremilast induced phosphorylation of plakoglobin at serine 665 - a mechanisms which is known to stabilize cardiomyocyte cohesion. Interestingly, keratinocytes phospho-deficient at this side showed altered organization of Dsg1, Dsg3 and keratin filaments and impaired adhesion, which was not rescued by apremilast. These data identified a new mechanism of desmosome regulation and propose that apremilast is protective in pemphigus by stabilizing keratinocyte cohesion.

cell biology↗