Biology subjects

Madsen, P.

Publications and source records attributed to Madsen, P..

8 recordsLinked to original sources

bioRxiv2025

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a rapidly emerging therapeutic strategy for difficult-to-drug cytosolic proteins. PROTACs are heterobifunctional small molecules that bridge the target with an E3 ubiquitin ligase, destining it for degradation by the proteasome. They have the potential to be orally available and to act catalytically, switching the pharmacology from occupancy-driven to event-driven (1-3). Here we present a strategy for targeted degradation of extracellular proteins by reshaping the interaction between the broadly expressed lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation with the target and sortilin, followed by endocytosis and lysosomal degradation. SORTAC activity can be genetically encoded as demonstrated by converting an IgG binding nanobody to an IgG degrading nanobody or by chemical conjugation, enabling single step conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, using structure-based design, we generated small molecule SORTACs against the inflammatory cytokine TNFa with nanomolar range potency and with physicochemical properties like PROTACs. Our results demonstrate that SORTACs constitute a versatile and highly modular platform for rapid generation of degraders of in theory any extracellular target and with the potential to have wide impact in drug discovery.

biochemistry↗

bioRxiv2025

Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation

The leukocyte common antigen related receptor (LAR) is a member of the LAR receptor protein tyrosine phosphatase (RPTP) family of synaptic adhesion molecules that contribute to the proper alignment and specialization of synaptic connections in the mammalian brain. LAR-RPTP members have been genetically associated with neuropsychiatric disorders, but the molecular consequences of genetic perturbations of LAR remain unstudied. Using exome sequencing data from psychiatric patients and controls, we identify rare missense variants of LAR that render the extracellular domain (ECD) unstable and susceptible to proteolytic cleavage. Using recombinant and cellular systems, we describe three variants that cause disruption of the LAR:NGL-3 interaction, which results in loss of transcellular adhesion and synaptogenic effects. Furthermore, we show that overexpression of two of these variants elicit altered morphological phenotypes in an imaging-based morphological profiling assay compared to wild type LAR, suggesting that destabilization of the LAR ECD has broad effects on LAR function. In conclusion, our study identifies three rare, missense variants in LAR that could provide insights into LAR involvement with psychiatric pathobiology.

neuroscience↗

bioRxiv2024

A triple serine motif in the intracellular domains of sortilin-related receptors SorCS1-3 regulates neurotrophic activity

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS1-3 intracellular domains (ICDs) contain a conserved triple serine motif that potentially functions as a signaling switch to induce neurotrophic signaling in hippocampal neurons. We demonstrate that phosphorylation mimicking mutations of the SorCS1-3 triple serine motifs display neurotrophic activity independently of both their extracellular domains (ECDs) and BDNF, and that the substitution of serines to alanines renders neurons less responsive to BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate downstream signaling kinases of the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide the first mechanistic insights into SorCS1-3 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active modulators.

neuroscience↗

bioRxiv2023

Comparative Phylogeography of Tree Species in the Hyrcanian Forests, Iran by Genome-wide SNPs

The Hyrcanian forests in Iran are one of the last remaining natural deciduous forests in the world and a UNESCO World Heritage site. We investigated the population genetics of representative indigenous tree species, Acer velutinum Boiss., Fagus orientalis Lipsky, and Quercus castaneifolia C.A. Mey. in northern Iran and also F. orientalis populations in the Euro-Siberian and Colchic sub-regions in northern Turkiye. We used the double-digest RAD-seq method and genotyped 90 populations and 1,589 individuals across the distribution range of the species. Our analyses yielded 1,347, 2,091, and 8,881 genome-wide SNPs from 28 populations of A. velutinum, 32 populations of F. orientalis, and 30 Q. castaneifolia, respectively. Our results revealed higher genetic differentiations among A. velutinum populations than those of F. orientalis and Q. castaneifolia within the Hyrcanian forests. The global FST value was lowest for F. orientalis populations (0.019) and highest for A. velutinum populations (0.12), while the FIS value was negative for A. velutinum (-0.095). Demographic history analysis indicated a bottleneck during the last glacial maximum for the A. velutinum populations with reduced effective population size. The three species showed evidence of population bottlenecks during the Pliocene. Our findings highlight the pronounced genetic divergence among A. velutinum populations in the Hyrcanian forests compared to the other two species, suggesting cryptic speciation. Conversely, F. orientalis and Q. castaneifolia populations demonstrated a reduced level of genetic structure, indicating that species-specific factors, such as pollen production and pollination efficiency, may have influenced the genetic patterns within these species in similar environments. We did not observe significant elevational genetic differentiation within populations of the studied species. Furthermore, the F. orientalis populations from Turkiye exhibited a distinct west-east genetic structure and were highly diverged from the Iranian F. orientalis populations.

evolutionary biology↗

bioRxiv2022

Comparison of selective genotyping strategies in genomic selection programs for broilers using stochastic simulation

Breeding programs using genomic information have become common in broilers. In broilers, the main traits for selection are body weight and feed efficiency. These traits are measured in both sexes and before sexual maturity. Thus, increases in genetic gain in broiler breeding programs due to the use of genomic information are attributable primarily to the increased accuracy of predicted breeding values of potential parents. As not all birds can be genotyped due to economic constraints, an optimal genotyping strategy needs to be chosen. The objective of this study was to investigate the rates of genetic gain and inbreeding obtained by varying three factors: the percentage of birds genotyped (PG), the percentage of birds genotyped randomly (PRG) or selectively, and the percentage of males among genotyped birds (PMG). Stochastic computer simulation with a full factorial experimental design was used. Significant interaction among the factors (PG, PRG, and PMG) was observed for the rate of genetic gain in body weight and aggregate breeding value, but not for the gain in residual feed intake or the rate of inbreeding per generation. Our findings indicate that the PG, PRG, and PMG need to be considered when selecting a genotyping strategy for a broiler breeding program. If available resources allow only to genotype a small percentage (e.g., 2.5% or 5%) of all birds, the genotyping of 50-100% of male birds and selection of birds to be genotyped using phenotypic information is best. If resources allow to genotype more (e.g., [≥]20%) candidates, genotyping of equal numbers of each sex, and low PRG level (i.e., preselection of the majority of candidate based on performance) is best. Provided that a proper genotyping strategy is chosen, we conclude that the incorporation of genomic information in broiler breeding programs can substantially increase the rate of genetic gain.

genetics↗

bioRxiv2020

SorCS1 binds the insulin receptor to enhance insulin sensitivity

Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.

physiology↗

bioRxiv2020

Inflight head stabilization associated with wingbeat cycle and sonar emissions in the Egyptian fruit bat.

Sensory processing of environmental stimuli during locomotion is critical for the successful execution of goal-directed behaviors and navigating around obstacles. The outcome of these sensorimotor processes can be challenged by head movements that perturb the sensory coordinate frames directing behaviors. In the case of visually-guided behaviors, visual gaze stabilization results from the integrated activity of the vestibuloocular reflex and motor efference copy originating within circuits driving locomotor behavior. A recent videographic study showed that echolocating bats exhibit inflight head stabilization during a target identification and landing task, though compensatory timing of the bats sonar signals was not reported. In the present investigation we tested hypotheses that head stabilization is more broadly implemented during epochs of exploratory flight, and is temporally associated with emitted sonar signals, which would optimize acoustic gaze. This was achieved by measuring head and body kinematics with motion sensors secured to the head and body of free-flying Egyptian fruit bats. These devices were integrated with ultrasonic microphones to record the bats sonar emissions and elucidate their temporal association with periods of head stabilization. Head accelerations in the Earth-vertical axis were asymmetric with respect to wing downbeat and upbeat relative to body accelerations. This indicated that inflight head and body accelerations were uncoupled, outcomes consistent with the implementation of head movements that limit vertical acceleration during wing downbeat. Furthermore, sonar emissions during stable flight occurred most often during wing downbeat and head stabilization, supporting the conclusion that head stabilization behavior optimized sonar gaze and environmental interrogation via echolocation. Summary statementDirect measurements of head and body kinematics from affixed motion sensors revealed head stabilization behaviors during exploratory flights in bats. Most sonar emissions were temporally correlated with this behavior, thereby contributing to the optimization of acoustic gaze.

animal behavior and cognition↗

bioRxiv2019

Comparison of different orders of Legendre polynomials in random regression model for estimation of genetic parameters and breeding values of milk yield in the Chinese Holstein population

Random regression test-day model has become the most commonly adopted model for routine genetic evaluations for different dairy populations, which allows accurately accounting for genetic and environmental effects at different periods during lactation. The objective of this study was to explore appropriate random regression test-day model for genetic evaluation of milk yield in Chinese Holstein population. Data included 419,567 test-day records from 54,417 cows in the first lactation. Variance components and breeding values were estimated using random regression test-day model with different order (first order to fifth order) of Legendre polynomials, and accounted for homogeneous or heterogeneous residual variance across the lactation. The goodness of fit of the models was evaluated by total residual variance (TRV) and - 2logL. Further, the predictive ability of the models was assessed by Spearmans rank correlation between estimated breeding values for 305d milk yield (EBV305) from the full data set and reduced data set in which the records from the last calving year were masked. The results showed that random regression models using third order Legendre polynomials (LP3) with heterogeneous residual variance achieved the lower TRV and - 2logL value and the highest correlation for EBV305 between full data and reduced data. Heritability estimated by this model was 0.250 for 305d milk yield and ranged from 0.163 to 0.304 for test-day milk yield. We suggest random regression model with Legendre polynomial of order 3 and accounting for heterogeneous residual variances could be an appropriate model to be used for genetic evaluation of milk yield for Chinese Holstein population.

genetics↗