Biology subjects

Adrian, M.

Publications and source records attributed to Adrian, M..

5 recordsLinked to original sources

bioRxiv2026

A scalable human neuron model of Alzheimer's disease relevant tauopathy reveals mechanisms linking Tau fibrillization to synaptic dysfunction

Tauopathies, including Alzheimer's disease, are driven by pathological aggregation of hyperphosphorylated Tau, which disrupts synaptic integrity, impairs neuronal communication, and contributes to cognitive decline. To dissect tauopathy pathogenesis and enable therapeutic discovery, reliable and scalable human iPSC-neuron models are essential. Here, we developed two complementary iPSC-derived neuron models: an endogenous Tau seeding model, in which neurons are challenged with pre-formed Tau fragments that form paired helical filament (PHF)-consistent structures, and a Tau-0N3R overexpression seeding model to accelerate pathology. Both models recapitulate hallmark features of tauopathy, including the progressive formation of intracellular, hyperphosphorylated, sarkosyl-insoluble, and conformationally altered Tau aggregates (AT8, MC1 positive), along with synaptic and neuronal dysfunction. Cryogenic electron tomography (cryo-ET) further revealed the morphology of Tau fibrils within cells, as well as the ultrastructure of Tau fibrils trapping synaptic vesicles in situ. Using this platform, we performed integrated phosphoproteomics, high-content screening, and functional validation to identify key pathways driving Tau aggregation. MARK2-mediated phosphorylation within Tau's microtubule-binding domain emerged as an early trigger of aggregation, confirmed by site-specific mutagenesis. In parallel, small molecules targeting the PI3K/mTOR/GSK3 pathway reduced aggregation and restored synaptic function, with GSK3 inhibition lowering phosphorylation at critical aggregation-driving sites on Tau. Together, these findings establish a physiologically relevant, scalable platform for therapeutic screening that connects Tau seed uptake, site-specific phosphorylation, fibril formation, and synaptic disruption, ultimately identifying mechanistically separable intervention points along the aggregation cascade.

cell biology↗

bioRxiv2026

Role of transposons in the specialization of Botrytis cinerea to grapevine: Insights into small RNAs and a new Starship

While transposable elements (TEs) are recognized as major drivers of fungal genome structure, evidence of their direct involvement in the interaction with host plants and the environment is only beginning to emerge. Retrotransposons can generate small RNA (sRNA) that act through cross-kingdom RNA interference, while giant DNA TEs called Starships carry dozens of cargo genes that enrich the accessory gene compartment of fungal genomes. In the polyphagous pathogen Botrytis cinerea, the Vv3 strain and other strains specialized on grapevine display a specific repertoire of TEs, including the retrotransposons BcCopia4, BcGypsy6, and BcGypsy7. This study first explored the putative role of sRNA generated from these retrotransposons in the interaction between the Vv3 strain and its host of origin, grapevine. Putative targets were identified among the host mRNAs, but predicted cleavage sites could not be experimentally validated. Moreover, Dicer mutants unable to produce retrotransposons-derived sRNA remained fully pathogenic on grapevine, indicating that these sRNAs do not act as virulence factors on this host. In parallel, this study provides an updated RNA-seq-based annotation of the accessory genes of the Vv3 strain, which revealed a new 93 kb-Starship harboring 43 cargo genes, some of which are related to arsenic resistance. A formal genetic approach confirmed that this locus confers resistance to this metalloid. This giant TE, named Ariane, was also detected in additional grapevine-specialized strains resistant to arsenic but not in strains isolated from other hosts such as tomato. In conclusion, this study highlights how a Starship giant transposon shaped the accessory genes compartment of the polyphagous fungus B. cinerea and may have contributed to its adaptation to vine cultivation by conferring resistance to arsenic, a compound widely used in vineyards during the last century. IMPACT STATEMENTFungal genomes contain many families of transposons whose functional role in adaptation to the environment and in biotic interactions remained hidden for a long time. In the grey mold fungus Botrytis cinerea, strains specialized on grapevine, such as Vv3, carry a specific repertoire of transposons which provides a valuable opportunity to investigate their role in niche adaptation. In this study, we first investigated retrotransposon-derived small RNA, previously described as effectors capable of manipulating the immunity of the model plant Arabidopsis thaliana. Although in silico analysis of the specific repertoire of small RNAs of the Vv3 strain suggested that some could target the expression of grapevine genes, a genetic approach demonstrated that they do not play a significant role in virulence on this host. In contrast, this study identified a new transposon, named Ariane, that carries 43 cargo genes and confers a selective advantage to the Vv3 strain. Ariane belongs to a family of giant transposons called Starships, recently discovered in fungi and considered to be responsible for horizontal genes transfers between unrelated species. Ariane was detected only in some B. cinerea strains isolated from grapevine, and a genetic cross showed that it provides these strains with the ability to grow in presence of arsenic. Arsenic was used in vineyards until the beginning of the 21st century to control fungal trunk diseases and insect pests. Therefore, Ariane appears to have played an important role in the adaptation of B. cinerea strains to cultivated grapevine. Overall, these results underline the importance of considering Starships when predicting emergence of resistance to antifungal compounds. DATA SUMMARYThe novel data described in this study, i.e., RNA-Seq data and the Starship element are accessible under NCBI GEO accession GSE327899 and at https://doi.org/10.57745/HYWRNM, respectively. All information related to Botrytis cinerea genomes used in this study are centralized and kept up to date at the Bioinfo Bioger genomic web portal: https://bioinfo.bioger.inrae.fr/portal/genome-portal/. Direct links to individual portals are respectively https://bioinfo.bioger.inrae.fr/portal/genome-portal/3/ for B. cinerea Vv3 genome, https://bioinfo.bioger.inrae.fr/portal/genome-portal/2/ for B. cinerea Sl3 genome, and https://bioinfo.bioger.inrae.fr/portal/genome-portal/4/ for B. cinerea populations isolated on tomato or grapevine. Each portal provides: (i) a centralized access to public genomic resources, including the genome, transposon, and RNA repositories; (ii) a data browser to download the genomic files; (iii) a genome browser that enables visualization of features within their genomic context, along with associated expression data. As a summary, the prior main public B. cinerea genomic accessions and resources used in this study are: GCA_039644125 for VV3 genome, GCA_022560135 for Sl3 genome, GCA_000143535 for B05.10 genome, PRJNA624742 for populations, https://doi.org/10.57745/HYWRNM for transposons, and GSE181592 for small RNAs. Furthermore, table S1 summarizes the list and characteristics of the 64 B. cinerea genomes publicly available to date. The genomic data for Vitis vinifera genome PN40024.v4 used in this study are available at: https://integrape.eu/resources/genes-genomes/genome-accessions/.

genomics↗

bioRxiv2026

Soma-seq links intracellular protein states to transcriptional programs in the human brain

Neurodegenerative disease is largely driven by pathological protein states, which cannot be fully inferred from transcript levels. Yet, joint measurement of cytoplasmic proteins and RNA in single cells from archival human brain tissue remains challenging. Here we present Soma-seq, a method integrating transcriptome and antibody-based intracellular protein measurements in single cells from frozen human brain tissue. Applying Soma-seq to Alzheimers disease cortex, we quantified multiple intracellular proteins, including hyperphosphorylated Tau, alongside RNA. Soma-seq resolves a continuous trajectory of pathological progression based on multiplexed protein measurements and reveals associated gene programs. CRISPR perturbation in human iPSC-derived neurons validates Soma-seq-derived candidates and identifies protective factors to Tau aggregation.

neuroscience↗

bioRxiv2023

Deficiency for scavenger receptors Stabilin-1 and Stabilin-2 leads to age-dependent renal and hepatic depositions of fasciclin domain proteins TGFBI and Periostin in mice

BackgroundStabilin-1 and Stabilin-2 are two major scavenger receptors of liver sinusoidal endothelial cells that mediate removal of diverse molecules from the plasma. Double-knockout mice (Stab-DKO) develop impaired kidney function and a decreased lifespan, while single Stabilin deficiency or therapeutic inhibition ameliorates atherosclerosis and Stab1-inhibition is subject of clinical trials in immuno-oncology. Although POSTN and TFGBI have recently been described as novel Stabilin ligands, the dynamics and functional implications of these ligands have not been comprehensively studied. MethodsImmunofluorescence, Western Blotting and Simple Western as well as in situ hybridization (RNAScope) und qRT-PCR were used to analyze transcription levels and tissue distribution of POSTN and TGFBI in Stab-KO mice. Stab-POSTN-Triple deficient mice were generated to assess kidney and liver fibrosis and function in young and aged mice. ResultsTGFBI and POSTN protein accumulated in kidney and liver tissue in Stab-DKO mice during aging despite unchanged transcriptional levels. Stab-POSTN-Triple KO mice showed glomerulofibrosis and a reduced lifespan comparable to Stab-DKO mice. However, alterations of the glomerular diameter and vascular density were partially normalized in Stab-POSTN-Triple KO. ConclusionTGFBI and POSTN are Stabilin-ligands that are deposited in an age-dependent manner in the kidneys and liver due to insufficient scavenging in the liver. Functionally, POSTN appears to partially contribute to the observed renal phenotype in Stab-DKO mice. This study provides details on downstream effects how how Stabilin dysfunction affects distant organs on a molecular and functional level.

molecular biology↗

bioRxiv2022

Targeting of scavenger receptors Stabilin-1 and Stabilin-2 ameliorates atherosclerosis by a plasma proteome switch mediating monocyte/macrophage suppression

BackgroundScavenger receptors (SR) Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are preferentially expressed by liver sinusoidal endothelial cells. They mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. Studies suggest that Stab1 and Stab2 may impact atherosclerosis. Although subsets of tissue macrophages also express Stab1, hematopoietic Stab1 deficiency does not modulate atherogenesis. Here, we comprehensively studied how targeting Stab1 and Stab2 affects atherosclerosis. MethodsApoE-KO mice were interbred with Stab1-KO and Stab2-KO mice and fed a Western diet (WD). For antibody targeting, Ldlr-KO mice were also used. Unbiased plasma proteomics were performed and independently confirmed. Ligand binding studies comprised GST-pull down and endocytosis assays. Plasma proteome effects on monocytes were studied by single cell RNA sequencing in vivo, and by gene expression analyses of Stabilin-ligand-stimulated and plasma-stimulated bone marrow-derived monocytes/macrophages (BMDM) in-vitro. ResultsSpontaneous and WD-associated atherogenesis was significantly reduced in ApoE-Stab1- and ApoE-Stab2-KO. Similarly, inhibition of Stab1 or Stab2 by monoclonal antibodies (mAB) significantly reduced WD-associated atherosclerosis in ApoE-KO and Ldlr-KO. While neither plasma lipid levels nor circulating immune cell numbers were decisively altered, plasma proteomics revealed a switch in the plasma proteome, consisting of 231 dysregulated proteins comparing Wildtype with Stab1/2 single and Stab1/2-double KO, and of 41 proteins comparing ApoE-, ApoE-Stab1- and ApoE-Stab2-KO. Among this broad spectrum of common, but also disparate SR ligand candidates, Periostin, Reelin and TGFBi, known to modulate atherosclerosis, were independently confirmed as novel circulating ligands of Stab1/2. scRNA-Seq of circulating myeloid cells of ApoE-, ApoE-Stab1- and ApoE-Stab2-KO showed transcriptomic alterations in patrolling (Ccr2-/Cx3cr1++/Ly6Clo) and inflammatory (Ccr2+/Cx3cr1+/Ly6Chi) monocytes including downregulation of pro-atherogenic transcription factor Egr1. In Wildtype BMDM, ligand exposure alone did not alter Egr1 expression in-vitro. However, exposure to plasma from ApoE-Stab1- and ApoE-Stab2-KO mice showed a reverted pro-atherogenic macrophage activation as compared to ApoE-KO plasma including downregulation of Egr1 in-vitro. ConclusionsInhibition of Stab1/Stab2 mediates an anti-inflammatory switch in the plasma proteome including direct Stabilin ligands. The altered plasma proteome suppresses both patrolling and inflammatory monocytes and, thus, systemically protects against atherogenesis. Altogether, anti-Stab1- and anti-Stab2-targeted therapies provide a novel approach for the future treatment of atherosclerosis. Clinical Perspective1) What is new?- Inhibition of evolutionary conserved class H scavenger receptors Stabilin-1 and Stabilin-2 reduces aortic plaque burden in preclinical models. - Atheroprotection is mediated likely through downregulation on transcriptional factor Egr1 in monocytes by multifaceted plasma protein changes. - Transforming growth factor, beta-induced (TGFBi), Periostin (POSTN) and Reelin (Reln) are novel ligands of Stabilin-1 and Stabilin-2 and are implicated in atherosclerosis development. 2) What are the clinical implications?- Monoclonal anti-Stab1- and anti-Stab2 antibodies provide a novel approach for the future treatment of atherosclerosis. - In the future, the plasma proteome composition may serve as a predictive factor, biomarker or surrogate parameter for cardiovascular disease in patients.

molecular biology↗