Biology subjects

Stoldt, M.

Publications and source records attributed to Stoldt, M..

4 recordsLinked to original sources

bioRxiv2023

Direct disassembly of alpha-syn preformed fibrils into native alpha-syn monomers by an all-D-peptide

Parkinsons disease (PD) is the most common neurodegenerative movement disorder worldwide. One of its central features is the neurodegeneration that starts in the substantia nigra and progressively tends to involve other brain regions. -Synuclein (-syn) and its aggregation during pathogenesis have been drawn into the center of attention, where especially soluble oligomeric and fibrillar structures are thought to play a key role in cell-to-cell transmission and induction of toxic effects. Here, we report the development of all-D-enantiomeric peptide ligands that bind monomeric -syn with high affinity, thereby stabilizing the physiological intrinsically disordered structure and preventing initiation of aggregation, and more important, disassembling already existing aggregates. This "anti prionic" mode of action (MoA) has the advantage over other MoAs that it eliminates the particles responsible for disease propagation directly and independently of the immune system, thereby restoring the physiological monomer. Based on mirror image phage display on the D-enantiomeric full-length -syn target, we identified SVD-1 and SVD-1a by next generation sequencing, Thioflavin-T screens and rational design. The compounds were analyzed with regard to their anti-aggregation potential and both compounds showed aggregation delaying as well as seed capacity reducing effects in de novo and seeded environments, respectively. High affinity towards the monomeric -syn, in the low nano- to picomolar KD range was identified by surface plasmon resonance (SPR). SVD-1a reduced toxic effects as well as intracellular seeding capacity of -syn pre-fromed fibrils (PFF) in cell culture. SVD-1a disassembled -syn PFF into monomers as identified by atomic force microscopy (AFM), time dependent dynamic light scattering (DLS) and size exclusion chromatography (SEC) analysis. The present work provides promising results on the development of lead compounds with this anti-prionic mode of action for treatment of Parkinsons disease and other synucleinopathies.

neuroscience↗

bioRxiv2023

The influence of parasite load on transcriptional activity and morphology of a cestode and its ant intermediate host

Parasites with complex life cycles are known to induce phenotypic changes in their intermediate hosts to increase transmission to the final host. The magnitude of these changes could increase with the number of parasites, which would be beneficial to co-infecting parasites. Yet, adverse effects of high parasite load (i.e., many parasites in a single host) might stress both hosts and parasites (e.g., through an increased immune response). We investigated the consequences of parasite load on the transcriptional activity and morphology of the cestode Anomotaenia brevis and its intermediate host, the ant Temnothorax nylanderi. We demonstrated that many differentially expressed host genes shifted with parasite load, and their functions indicate a stronger immune response and fight against oxidative stress in heavily infected hosts. The expression of other host genes responded to infection in an all-or-nothing manner, as did the morphology of the host workers. However, the cestodes became smaller when they competed with other parasites for resources from a single host. Their expression profile further indicated shifts in host immune avoidance, starvation resistance and vesicle-mediated transport. In summary, our study reveals clear consequences of parasite load and highlights specific processes and traits affected by this.

evolutionary biology↗

bioRxiv2022

What doesn't kill you makes you live longer - Longevity of a social host linked to parasite proteins

Parasites with complex lifecycles often manipulate the phenotype of their intermediate hosts to increase the probability of transmission to their definitive hosts. Infection with Anomotaenia brevis, a cestode that uses Temnothorax nylanderi ants as intermediate hosts, leads to a multiple-fold extension of host lifespan and to changes in behaviour, morphology, and colouration. The mechanisms behind these changes are unknown, as is whether the increased longevity is achieved through parasite manipulation. Here we demonstrate that the parasite releases proteins into its host with functions that might explain the observed changes. These parasitic proteins make up a substantial portion of the proteome of the hosts haemolymph, and thioredoxin peroxidase and superoxide dismutase, two antioxidants, exhibited the highest abundances among them. The largest part of the secreted proteins could not be annotated, indicating they are either novel or severely altered during recent coevolution to function in host manipulation. We also detected shifts in the hosts proteome with infection, in particular an overabundance of vitellogenin-like-A in infected ants, a protein that regulates division of labour in Temnothorax ants, which could explain the observed behavioural changes. Our results thus point at two different strategies likely employed by this parasite to manipulate its host - by secretion of proteins with immediate influence on the hosts phenotype and by altering the hosts translational activity. Our findings reveal the intricate molecular interplay required to influence the phenotype of a host and shed light on potential signalling pathways and genes involved in parasite-host communication.

evolutionary biology↗

bioRxiv2021

Identification of functional residues using machine learning provides insights into the evolution of odorant receptor gene families in solitary and social insects

The gene family of insect odorant receptors (ORs) has greatly expanded in the course of evolution. ORs allow insects to detect volatile chemicals and therefore play an important role in social interactions, the detection of enemies and preys, and during foraging. The sequences of several thousand ORs are known, but their specific function or ligands have been identified only for very few of them. To advance the functional characterization of ORs, we compiled, curated and aligned the sequences of 3,902 ORs from 21 insect species. We identified the amino acid positions that best predict the response to ligands using machine learning on sets of functionally characterized proteins from the fly Drosophila melanogaster, the mosquito Anopheles gambiae and the ant Harpegnathos saltator. We studied the conservation of these predicted relevant residues across all OR subfamilies and show that the subfamilies that expanded strongly in social insects exhibit high levels of conservation in their binding sites. This indicates that ORs of social insect families are typically finely tuned and exhibit a sensitivity to very similar odorants. Our novel approach provides a powerful tool to use functional information from a limited number of genes to investigate the functional evolution of large gene families.

bioinformatics↗