Biology subjects

Jongsma, E.

Publications and source records attributed to Jongsma, E..

3 recordsLinked to original sources

bioRxiv2022

Removal of extracellular human amyloid beta aggregates by extracellular proteases in C. elegans

The amyloid-beta (A{beta}) plaques found in Alzheimers disease (AD) patients brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence A{beta} aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human A{beta}1-42. This secreted A{beta} forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human A{beta} aggregation regulators, we identified different collagens to ameliorate or potentiate A{beta} aggregation. We show that a disintegrin and metalloprotease ADM-2, an orthologue of ADAM9, reduces the load of extracellular A{beta} aggregates. ADM-2 is required and sufficient to remove the extracellular A{beta} aggregates. Thus, we provide in-vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular A{beta} aggregate removal. HighlightsExtracellular aggregates of amyloid beta are a hallmark of Alzheimers disease. Here we developed a novel C. elegans transgenic line that secretes human amyloid beta, which forms aggregates in the extracellular matrix (ECM). We show that ECM dynamics can disturb aggregation and that ADM-2, an ortholog of Human ADAM9, is involved in removing these extracellular aggregates.

cell biology↗

bioRxiv2021

Youthful and age-related matreotypes predict drugs promoting longevity

The identification and validation of drugs that promote health during aging ( geroprotectors) is key to the retardation or prevention of chronic age-related diseases. Here we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this novel observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a youthful matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for C. elegans longevity. With this reporter, we were able to eliminate false positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging. HighlightsO_LIMany geroprotective drugs alter extracellular matrix gene expression C_LIO_LIDefined young and old human matreotype signatures can identify novel potential geroprotective compounds C_LIO_LIProlonged collagen homeostasis as a surrogate marker for longevity C_LI

pharmacology and toxicology↗

bioRxiv2017

Mutations in C. elegans neuroligin-like glit-1, the apoptosis pathway and the calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-OHDA treatment

The loss of dopaminergic neurons is a hallmark of Parkinsons disease, the aetiology of which is associated with increased levels of oxidative stress. We used C. elegans to screen for genes that protect dopaminergic neurons against oxidative stress and isolated glit-1 (gliotactin (Drosophila neuroligin-like) homologue). Loss of the C. elegans neuroligin-like glit-1 causes increased dopaminergic neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), an oxidative- stress inducing drug that is specifically taken up into dopaminergic neurons. Furthermore, glit-1 mutants exhibit increased sensitivity to oxidative stress induced by H2O2 and paraquat. We provide evidence that GLIT-1 acts in the same genetic pathway as the previously identified tetraspanin TSP-17. After exposure to 6-OHDA and paraquat, glit-1 and tsp-17 mutants show almost identical, non-additive hypersensitivity phenotypes and exhibit highly increased induction of oxidative stress reporters. TSP-17 and GLIT-1 are both expressed in dopaminergic neurons. In addition, the neuroligin-like GLIT-1 is expressed in pharynx, intestine and several unidentified cells in the head. GLIT-1 is homologous, but not orthologous to neuroligins, transmembrane proteins required for the function of synapses. The Drosophila GLIT-1 homologue Gliotactin in contrast is required for epithelial junction formation. We report that GLIT-1 likely acts in multiple tissues to protect against 6-OHDA, and that the epithelial barrier of C. elegans glit-1 mutants does not appear to be compromised. We further describe that hyperactivation of the SKN-1 oxidative stress response pathway alleviates 6-OHDA-induced neurodegeneration. In addition, we find that mutations in the canonical apoptosis pathway and the calcium chaperone crt-1 cause increased 6-OHDA-induced dopaminergic neuron loss. In summary, we report that the neuroligin-like GLIT-1, the canonical apoptosis pathway and the calreticulin CRT-1 are required to prevent 6-OHDA-induced dopaminergic neurodegeneration.\n\nAuthor summaryNeurons use dopamine as a chemical messenger to mediate diverse behaviours. The gradual loss of dopaminergic neurons in specific brain areas is a hallmark of Parkinsons disease. The increased occurrence of highly reactive oxygen radicals, also called oxidative stress, is assumed to contribute to the demise of dopaminergic neurons. In this study we searched for genes that protect dopaminergic neurons against oxidative stress. We used the nematode C. elegans, a well- characterised model organism whose dopamine signalling system is very similar to that of humans. When C. elegans is exposed to 6-hydroxydopamine, an oxidative stress-inducing compound, dopaminergic neurons gradually die. Our major findings include: (i) absence of the neuroligin-like gene glit-1 causes highly increased cell death of dopaminergic neurons after 6-OHDA exposure; (ii) GLIT-1 acts in a similar manner as the previously identified tetraspanin TSP-17; (iii) GLIT-1 and TSP-17 also protect C. elegans from other types of oxidative stress; and (iv) the programmed cell death pathway and a calcium chaperone protect dopaminergic neurons as well. Collectively, this study shows that apoptosis proteins, the calcium chaperone CRT-1 and the neuroligin-like GLIT-1 protect against neurodegeneration after oxidative stress exposure.

genetics↗