Biology subjects

Thompson, T. B.

Publications and source records attributed to Thompson, T. B..

17 recordsLinked to original sources

bioRxiv2026

GDF3 is an endogenous antagonist of the ActE-ALK7/ACVR2 pathway in adipocytes

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) arise, in part, from excessive free fatty acid flux from adipose tissue to the liver. Activin E (ActE, encoded by INHBE) suppresses adipocyte lipolysis through the type I receptor ALK7 (ACVR1C). Loss-of-function variants in INHBE and ACVR1C reduce waist-to-hip ratio in humans, yet genetic knockouts in mice produce insulin resistance and hepatic steatosis, suggesting discrepancies between human and mouse biology. We identify GDF3, a TGF-{beta} superfamily ligand upregulated in obese adipose tissue, as the principal endogenous antagonist of ActE/ALK7 signaling. Human transcriptomic datasets reveal coordinated dysregulation: hepatic INHBE expression and circulating ActE protein are elevated in obesity, while adipose ACVR1C is downregulated and GDF3 is reciprocally upregulated. Using ALK7-selective reporter assays, we show GDF3 inhibits ActE-driven SMAD2/3 signaling as a competitive antagonist rather than the weak agonist previously proposed. ActE suppressed beta-adrenergic-stimulated lipolysis in mouse and human adipocytes and primary human adipose tissue; GDF3 overexpression abolished this effect. In diet-induced obese mice, inducible Gdf3 deletion reduced adipose lipolysis, resolved hepatic steatosis and fibrosis, and improved insulin sensitivity, benefits abolished by Inhbe knockdown, confirming dependence on ActE signaling. Predicted loss-of-function variants in INHBE show only nominal, WHR-dependent associations with type 2 diabetes risk, potentially confounded by hematological effects on HbA1c. Gdf3 deficiency synergized with the clinical-stage anti-activin receptor antibody Bimagrumab to amplify fat-mass loss and improve glucose homeostasis in multiple MASH models. These findings establish GDF3 as an endogenous antagonist of ActE-ALK7 signaling and nominate GDF3 inhibition as a therapeutic strategy for MASLD/MASH.

physiology↗

bioRxiv2026

Dynamical Aβ-Tau-Neurodegeneration Model Predicts Alzheimer's Disease Mechanisms and Biomarker Progression

Alzheimers disease is characterised by the pathological interaction of two proteins, amyloid-beta (A{beta}) and tau, which collectively drive neurodegeneration and cognitive decline. The progression of A{beta}, tau, and neurodegeneration biomarkers is captured by the ATN framework, which is a powerful tool for disease classification. However, since the ATN framework is mainly descriptive, it cannot quantify or predict relationships between biomarkers over time. We address this limitation by introducing a dynamical ATN (dATN) model that mechanistically simulates the spatiotemporal progression of A{beta}, tau, and neurodegeneration. The dATN model integrates mechanisms of prion-like protein aggregation of A{beta} and tau, network-based tau propagation, A{beta}-driven catalysis of tau progression, and tau-driven neurodegeneration. We calibrated the model using multimodal longitudinal imaging data from both the ADNI and BioFINDER-2 cohorts and show that it accurately fits longitudinal regional A{beta}, tau, and neurodegeneration data. Using the dATN model, we show that A{beta}-induced effects predict Braak-like cortical tau progression, that the spatial colocalisation of A{beta} and tau is a crucial biomarker of disease acceleration, and that tau-driven atrophy strongly correlates with observed neurodegeneration. Furthermore, by integrating the disease progression model with pharmacokinetic-pharmacodynamic simulations, we present a powerful tool that facilitates regional evaluation of therapeutic strategies targeting A{beta}, identification of critical intervention windows, and prediction of heterogeneous treatment effects across brain regions. This framework unifies mechanistic understanding with clinical imaging biomarkers, offering a quantitative approach for forecasting disease progression, testing mechanistic hypotheses, and optimising personalised treatment strategies in AD. One Sentence SummaryColocalisation of A{beta} and tau predicts regional tau progression and optimal A{beta}-targeted intervention windows, while tau predicts neurodegeneration.

neuroscience↗

bioRxiv2025

The crystal structure of the activin B:Fst288 complex and computational insights into the broad antagonistic activity and specificity of follistatin

Members of the TGF-{beta} family regulate diverse biological processes, and their activity is tightly controlled by extracellular antagonists such as follistatin 288 (Fst288). Fst288 potently inhibits activins A and B, GDF8, and GDF11. Among these, ActB is the least structurally and functionally characterized, which limits a full understanding of Fst288s broad activity and its specificity for this TGF-{beta} subgroup. To address this, we solved the crystal structure of the ActB:Fst288 complex. As in other complexes, two Fst288 molecules surround ActB, occluding both receptor-binding sites. However, ActB engages Fst288 differently: its fingers bind most strongly the ND domain, while its acidic fingertips uniquely contact FSD3 disrupting interactions between the two Fst288 molecules and reducing the cooperativity seen in other complexes. Computational analysis revealed that, although ActB exhibits higher interaction enthalpy, entropic penalty lowers its overall affinity compared to ActA, consistent with experimentally measured Kd values. We therefore propose that broad ligand inhibition by Fst288 arises from variations in binding interactions and the utilization of cooperativity when direct contacts are insufficient for high affinity. In cellular contexts, antagonistic effectiveness is further impacted by interactions between complexes and the extracellular matrix, resulting in comparable in vitro IC50 values. Finally, sequence comparisons with non-binding TGF-{beta}s indicate that Fst288 specificity originates from ionic contacts with acidic ligand fingertips which likely initiate recognition, while interactions at the type I and II interfaces stabilize the complex. This study provides deeper insight into Fst288s regulation of activin signaling and paves the way for designing inhibitors with desired selectivity.

molecular biology↗

bioRxiv2025

Heterogeneity in human brain clearance adds resilience against tauopathy -- a computational model informed by glymphatic MRI

Neurotoxic protein fragments such as amyloid-beta and tau accumulate in characteristic staging patterns in Alzheimers disease (AD). The brain clears such metabolic substances via multiple different systems, including via the glymphatic (extracellular/extravascular) pathway. Here, we ask how the distinct features that characterize human glymphatic function would affect the prion-like cascade of protein invasion associated with AD. To address this question, we extract and analyze individual clearance rates from human glymphatic MRI (gMRI) data sets. These clearance rates define subject-specific maps of glymphatic clearance that vary both across cortical lobes and Braak staging regions. We apply these clearance maps as initial states in a computational network model linking misfolded proteins, tissue damage, and local clearance to simulate a series of individual proteinopathy trajectories. Our results show that the spatial heterogeneity in initial clearance induces characteristic propagation patterns, delaying and redirecting the disease progression. Moreover, reducing this spatial heterogeneity accelerates disease progression and induces staging patterns typically associated with AD. A comparison between well-rested subjects and subjects who underwent a single night of sleep deprivation did not reveal differences in initial clearance maps nor in simulated disease progression. These findings suggest that spatial heterogeneity in brain clearance may be a key factor for neurodegenerative resilience.

neuroscience↗

bioRxiv2024

Structural Basis of Non-Latent Signaling by the Anti-Mullerian Hormone Procomplex

Most TGF{beta} family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Mullerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet remains active. Using single particle EM methods, we show the AMH prodomain consists of two subdomains: a vestigial TGF{beta} prodomain-like fold and a novel, helical bundle GF-binding domain, the result of an exon insertion 450 million years ago, that engages both receptor epitopes. When associated with the prodomain, the AMH GF is distorted into a strained, open conformation whose closure upon bivalent binding of AMHR2 displaces the prodomain through a conformational shift mechanism to allow for signaling.

molecular biology↗

bioRxiv2023

Personalised Regional Modelling Predicts Tau Progression in the Human Brain

Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimers disease, and its accumulation exhibits a rich spatio-temporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatio-temporal process is orchestrated - namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production or both. To address this, we develop a mechanistic model from tau PET data to describe tau dynamics along the Alzheimers disease timeline. Our analysis reveals longitudinal changes in production and transport dynamics on two independent cohorts, with subjects in early stage of the disease exhibiting transport-dominated spread, consistent with an initial spread of pathologic tau seeds, and subjects in late stage disease (Braak stage 3/4 onwards) characterised primarily by local production of tau. Furthermore, we demonstrate that the model can accurately predict subject-specific longitudinal tau accumulation at a regional level, potentially providing a new clinical tool to monitor and classify patient disease progression. TeaserA mechanistic model reveals tau protein dynamics in Alzheimers, showing stage-specific shifts in transport and local production.

neuroscience↗

bioRxiv2023

Activin E is a TGFβ ligand that signals specifically through activin receptor-like kinase 7.

Activins are one of the three distinct subclasses within the greater Transforming Growth Factor {beta} (TGF{beta}) superfamily. First discovered for their critical roles in reproductive biology, activins have since been shown to alter cellular differentiation and proliferation. At present, members of the activin subclass include activin A (ActA), ActB, ActC, ActE, and the more distant members myostatin and GDF11. While the biological roles and signaling mechanisms of most activins class members have been well-studied, the signaling potential of ActE has remained largely unknown. Here, we characterized the signaling capacity of homodimeric ActE. Molecular modeling of the ligand:receptor complexes showed that ActC and ActE shared high similarity in both the type I and type II receptor binding epitopes. ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. In mature murine adipocytes, ActE invoked a SMAD2/3 response via ALK7, similar to ActC. Collectively, our results establish ActE as an ALK7 ligand, thereby providing a link between genetic and in vivo studies of ActE as a regulator of adipose tissue. SignificanceActivin E is a homodimeric member of the TGF{beta} family belonging to the activin subclass. Currently, the signaling capacity of ActE is unknown due to a lack of reliable reagents to study the protein. Here, we demonstrate that ActE acts as a canonical TGF{beta} ligand that signals through SMAD2/3 in an ALK7-dependent manner, similar to ActC. ActE also utilizes the activin type II receptors, ActRIIA and ActRIIB, to signal and is unable to be antagonized by FS288 and WFIKKN2. This study shows that ActE is a signaling ligand and provides a connection between genetic and in vivo studies that links ActE to adiposity.

biochemistry↗

bioRxiv2023

Characterization of erythroferrone oligomerization and its impact on BMP antagonism

Hepcidin, a peptide hormone that negatively regulates iron metabolism, is expressed by bone morphogenetic protein (BMP) signaling. Erythroferrone (ERFE) is an extracellular protein that binds and inhibits BMP ligands, thus positively regulating iron import by indirectly suppressing hepcidin. This allows for rapid erythrocyte regeneration after blood loss. ERFE belongs to the C1Q/TNF related protein (CTRP) family and is suggested to adopt multiple oligomeric forms: a trimer, a hexamer, and a high molecular weight species. The molecular basis for how ERFE binds BMP ligands and how the different oligomeric states impact BMP inhibition are poorly understood. In this study, we demonstrated that ERFE activity is dependent on the presence of stable dimeric or trimeric ERFE, and that larger species are dispensable for BMP inhibition. Additionally, we used an in-silico approach to identify a helix, termed the ligand binding domain (LBD), that was predicted to bind BMPs and occlude the type I receptor pocket. We provide evidence that the LBD is crucial for activity through luciferase assays and surface plasmon resonance (SPR) analysis. Our findings provide new insight into how ERFE oligomerization impacts BMP inhibition, while identifying critical molecular features of ERFE essential for binding BMP ligands.

molecular biology↗

bioRxiv2022

Functional substitutions of amino acids that differ between GDF11 and GDF8 impact skeletal development and skeletal muscle.

Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGF{beta} family proteins that interact with nearly identical signaling receptors and antagonist proteins. However, GDF11 appears to activate SMAD2/3 in vitro and in vivo more potently than GDF8. The ligands possess divergent structural properties, whereby substituting unique GDF11 amino acids into GDF8 enhanced activity of the resulting chimeric GDF8. We investigated potentially distinct endogenous activities of GDF11 and GDF8 in vivo by genetically modifying their mature signaling domains. Full recoding of the GDF8 mature domain to that of GDF11 yielded mice lacking GDF8, with GDF11 levels [~]50-fold higher than normal, and exhibiting modestly decreased muscle mass, with no apparent negative impacts on health or survival to adulthood. Substitution of two specific amino acids in the fingertip region of GDF11 with the corresponding GDF8 residues resulted in prenatal axial skeletal transformations, consistent with Gdf11-deficient mice, without apparent perturbation of skeletal or cardiac muscle development or homeostasis. These experiments uncover distinctive features between the GDF11 and GDF8 mature domains in vivo and identify specific requirement for GDF11 in early-stage skeletal development. Summary StatementReplacement of amino acids unique to GDF11 and GDF8 into the native locus of the other ligand yields measurable, differential skeletal and muscle phenotypes, revealing distinct features between the ligands.

developmental biology↗

bioRxiv2022

The role of clearance in neurodegenerative diseases

Alzheimers disease, the most common form of dementia, is a systemic neurological disorder associated with the formation of toxic, pathological aggregates of proteins within the brain that lead to severe cognitive decline, and eventually, death. In normal physiological conditions, the brain rids itself of toxic proteins using various clearance mechanisms. The efficacy of brain clearance can be adversely affected by the presence of toxic proteins and is also known to decline with age. Motivated by recent findings, such as the connection between brain cerebrospinal fluid clearance and sleep, we propose a mathematical model coupling the progression of toxic proteins over the brains structural network and protein clearance. The model is used to study the interplay between clearance in the brain, toxic seeding, brain network connectivity, aging, and progression in neurodegenerative diseases such as Alzheimers disease. Our findings provide a theoretical framework for the growing body of medical research showing that clearance plays an important role in the etiology, progression and treatment of Alzheimers disease.

neuroscience↗

bioRxiv2022

Front propagation and arrival times in networks with application to neurodegenerative diseases

Many physical, epidemiological, or physiological dynamical processes on networks support front-like propagation, where an initial localized perturbation grows and systematically invades all nodes in the network. A key question is then to extract estimates for the dynamics. In particular, if a single node is seeded at a small concentration, when will other nodes reach the same initial concentration? Here, motivated by the study of toxic protein propagation in neurodegenerative diseases, we present and compare three different estimates for the arrival time in order of increasing analytical complexity: the linear arrival time, obtained by linearizing the underlying system; the Lambert time, obtained by considering the interaction of two nodes; and the nonlinear arrival time, obtained by asymptotic techniques. We use the classic Fisher-Kolmogorov-Petrovsky-Piskunov equation as a paradigm for the dynamics and show that each method provides different insight and time estimates. Further, we show that the nonlinear asymptotic method also gives an approximate solution valid in the entire domain and the correct ordering of arrival regions over large regions of parameters and initial conditions.

biophysics↗

bioRxiv2021

Predicting brain atrophy from tau pathology: A summary of clinical findings and their translation into personalized models

For more than 25 years, the amyloid hypothesis-the paradigm that amyloid is the primary cause of Alzheimers disease-has dominated the Alzheimers community. Now, increasing evidence suggests that tissue atrophy and cognitive decline in Alzheimers disease are more closely linked to the amount and location of misfolded tau protein than to amyloid plaques. However, the precise correlation between tau pathology and tissue atrophy remains unknown. Here we integrate multiphysics modeling and Bayesian inference to create personalized tau-atrophy models using longitudinal clinical images from the the Alzheimers Disease Neuroimaging Initiative. For each subject, we infer three personalized parameters, the tau misfolding rate, the tau transport coefficient, and the tau-induced atrophy rate from four consecutive annual tau positron emission tomography scans and structural magnetic resonance images. Strikingly, the tau-induced atrophy coefficient of 0.13/year (95% CI: 0.097-0.189) was fairly consistent across all subjects suggesting a strong correlation between tau pathology and tissue atrophy. Our personalized whole brain atrophy rates of 0.68-1.68%/year (95% CI: 0.5-2.0) are elevated compared to healthy subjects and agree well with the atrophy rates of 1-3%/year reported for Alzheimers patients in the literature. Once comprehensively calibrated with a larger set of longitudinal images, our model has the potential to serve as a diagnostic and predictive tool to estimate future atrophy progression from clinical tau images on a personalized basis.

biophysics↗

bioRxiv2021

Braiding Braak and Braak: Staging patterns and model selection in network neurodegeneration

A hallmark of Alzheimers disease is the aggregation of insoluble amyloid-beta plaques and tau protein neurofibrillary tangles. A key histopathological observation is that tau protein aggregates follow a structured progression pattern through the brain. Mathematical network models of prion-like propagation have the ability to capture such patterns but a number of factors impact the observed staging result, thus introducing questions regarding model selection. Here, we introduce a novel approach, based on braid diagrams, for studying the structured progression of a marker evolving on a network. We apply this approach to a six-stage Braak patternof tau proteins, in Alzheimers disease, motivated by a recent observation that seed-competent tau precedes tau aggregation. We show that the different modeling choices, from the model parameters to the connectome resolution, play a significant role in the landscape of observable staging patterns. Our approach provides a systematic way to approach model selection for network propagation of neurodegenerative diseases that ensures both reproducibility and optimal parameter fitting. Author summaryNetwork diffusion models of neurodegenerative diseases are a class of dynamical systems that simulate the evolution of toxic proteins on the connectome. These models predict, from an initial seed, a pattern of invasion called staging. The generalized staging problem seeks to systematically study the effect of various model choices on staging. We introduce methods based on braid diagrams to test the possible staging landscape of a model and how it depends on the choice of connectome, as well as the model parameters. Our primary finding is that connectome construction, the choice of the graph Laplacian, and transport models all have an impact on staging that should be taken into account in any study.

neuroscience↗

bioRxiv2020

Deletion of Gremlin-2 alters estrous cyclicity and disrupts female fertility in mice

Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which are known to have key functions during embryogenesis and adult physiology. While BMPs play essential roles in adult female reproductive physiology, the role of the DAN family in ovarian function is less understood. We generated mice null for Grem2 to study its role in female fertility in addition to screening patients with primary ovarian insufficiency for variants in GREM2. Grem2-/- mice are viable and female Grem2-/- mice have diminished fecundity and irregular estrous cycles. This is accompanied by reduced serum levels of anti-Mullerian hormone, a marker of the ovarian reserve, in adult mice. Alterations in ovarian expression of inhibin and activin subunit genes, which are required for regulation of the hypothalamic-pituitary-ovarian (HPO) axis, were identified. While Grem2 mRNA transcript was not detected in the pituitary, Grem2 was expressed in the hypothalami of wild type female mice. Additionally, screening 106 women with primary ovarian insufficiency identified one individual with a heterozygous variant in GREM2 that lies within the predicted BMP-GREM2 interface. In total, these data suggest that Grem2 is necessary for female fecundity by playing a novel role in regulating the HPO axis and possibly contributing to female reproductive disease.

physiology↗

bioRxiv2020

Protein-protein interactions in neurodegenerative diseases: a conspiracy theory.

Neurodegenerative diseases such as Alzheimers or Parkinsons are associated with the prion-like propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimers disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modeling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics. Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this theoretical model to test the possible interactions between tau proteins and amyloid-beta and study the resulting coupled behavior between toxic protein clearance and proteopathic phenomenology. Our analysis reveals ways in which amyloid-beta and tau proteins may conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease. Author SummaryIn 1906 Dr. Alois Alzheimer delivered a lecture to the Society of Southwest German Psychiatrists. Dr. Alzheimer presented the case of Ms. Auguste Deter; her symptoms would help to define Alzheimers disease (AD). Over a century later, with an aging world population, AD is at the fore of global neurodegenerative disease research. Previously, toxic amyloid-beta protein (A{beta}) was thought to be the primary driver of AD development. Recent research suggests that another protein, tau, plays a fundamental role. Toxic tau protein contributes to cognitive decline and appears to interact with toxic A{beta}; research suggests that toxic A{beta} may further increase the effects of toxic tau. Theoretical mathematical models are an important part of neurodegenerative disease research. Such models: enable extensible computational exploration; illuminate emergent behavior; and reduce research costs. We have developed a novel, theoretical mathematical model of two interacting species of proteins within the brain. We analyze the mathematical model and demonstrate a computational implementation in the context of A{beta}-tau interaction in the brain. Our model clearly suggests that: the removal rate of toxic protein plays a critical role in AD; and the A{beta}-tau conspiracy theory is a nuanced, and exciting path forward for Alzheimers disease research.

neuroscience↗

bioRxiv2019

The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild type ACVR1. To explore the role of the NSC, we generated agonist-only Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSCs physiological role in corresponding knock-in mice. Impact StatementThe non-signaling complex formed by Activin A and ACVR1 is operant in vivo and is required to temper the degree of heterotopic ossification in the genetic disorder fibrodysplasia ossificans progressiva.

cell biology↗

bioRxiv2017

Structure of the human pro-myostatin precursor and determinants of growth factor latency

Myostatin, a key regulator of muscle mass in vertebrates, is biosynthesised as a latent precursor in muscle and is activated by sequential proteolysis of the pro-domain. To investigate the molecular mechanism by which pro-myostatin remains latent, we have solved the structure of unprocessed promyostatin and analysed the properties of the protein in its different forms. Crystal structures and SAXS analyses show that pro-myostatin adopts an open, V-shaped structure with a domain-swapped arrangement. The pro-mature complex, after cleavage of the furin site, has significantly reduced activity compared with mature growth factor and persists as a stable complex that is resistant to the natural antagonist follistatin. The latency appears to be conferred by a number of distinct features that collectively stabilise the interaction of the pro-domains with the mature growth factor, enabling a regulated step-wise activation process, distinct from the prototypical pro-TGF-{beta}1. These results provide a basis for understanding the effect of missense mutations in pro-myostatin and pave the way for the design of novel myostatin inhibitors.

biochemistry↗