Biology subjects

Frenkel, D.

Publications and source records attributed to Frenkel, D..

4 recordsLinked to original sources

bioRxiv2024

Self-reactive B cells traverse a perfect storm of somatic mutagenesis to cause a virus-induced autoimmune disease

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-CV). We traced the evolution of the pathogenic rheumatoid factor (RhF) autoantibodies in four HCV-CV patients by deep single cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive accumulation of a large disease causing clone. A sensitive method for quantifying low affinity binding revealed three recurring heavy/light chain combinations created by V(D)J recombination bound self IgG but not viral E2 antigen. Whole genome sequencing revealed accumulation of thousands of somatic mutations, at levels comparable to CLL and normal memory B cells, but with 1-2 corresponding to driver mutations found recurrently in B cell leukemia/lymphoma. V(D)J hypermutation created autoantibodies with compromised solubility. In this virus-induced autoimmune disease, infection promotes a perfect storm of somatic mutagenesis in the descendants of a single B cell.

immunology↗

bioRxiv2023

Self-replication of Abeta42 aggregates occurs on small and isolated fibril sites

Self-replication of amyloid fibrils via secondary nucleation is an intriguing physicochemical phenomenon in which existing fibrils catalyse the formation of their own copies. The molecular events behind this fibril surface-mediated process remain largely inaccessible to current structural and imaging techniques. Using statistical mechanics, computer modelling, and chemical kinetics, we show that the catalytic structure of the fibril surface can be inferred from the aggregation behaviour in the presence and absence of a fibril-binding inhibitor. We apply our approach to the case of Alzheimers A{beta}42 amyloid fibrils formed in the presence of proSP-C Brichos inhibitors. We find that self-replication of A{beta}42 fibrils occurs on small catalytic sites on the fibril surface, which are far apart from each other, and each of which can be covered by a single Brichos inhibitor.

biophysics↗

bioRxiv2020

Oligonucleotides can act as superscaffolds that enhance liquid-liquid phase separation of intracellular mixtures

Intracellular liquid-liquid phase separation (LLPS) enables the formation of biomolecular condensates, which play a crucial role in the spatiotemporal organisation of biomolecules (proteins, oligonucleotides). While LLPS of biopolymers has been demonstrated in both experiments and computer simulations, the physical determinants governing phase separation of protein-oligonucleotide systems are not fully understood. Here, we introduce a minimal coarse-grained model to investigate concentration-dependent features of protein-oligonucleotide mixtures. We demonstrate that adding oligonucleotides to biomolecular condensates composed of oligonucleotide-binding scaffold proteins enhances LLPS; since oligonucleotides act as ultra-high-valency molecules (termed superscaffolds) that increase the molecular connectivity among scaffold proteins. Importantly, we find that oligonucleotides promote protein LLPS via a seeding-type mechanism; recruiting numerous protein molecules and reducing the thermodynamic and kinetic barriers for nucleation and phase separation. By probing the conformational properties of oligonucleotides within droplets, we show that these biopolymers can undergo phase separation-driven compaction, which may be entropic in nature. Finally, we provide a quantitative comparison between mixture composition, protein valency, and protein-oligonucleotide interaction strengths. We find that superscaffolds preferentially recruit higher valency proteins to condensates, and that multiphase immiscibility within condensates can be achieved by modulating the relative protein-oligonucleotide binding strengths. These results shed light on the roles of oligonucleotides in ribonu-cleoprotein granule formation, heterochromatin compaction, and internal structuring of the nucleolus and stress granules.

biophysics↗

bioRxiv2019

Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

Alterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimers disease (AD). We had shown impairments in the ability of aged astrocytes isolated from 5xFAD mice to clear and uptake amyloid-{beta} (A{beta}) as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In this study, we predicted that with age, astrocytes in 5xFAD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to A{beta} plaques in 5xFAD mice. Inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells reduced interelukin-6 secretion by senescent astrocytes and resulted in improved neuronal support. Moreover, senescent astrocytes exhibited an increase in the induction of the TGF-{beta}1-SMAD2/3 pathway, and inhibition of this pathway resulted in a reduction of cellular senescence. We also discovered that soluble A{beta}42 induced astrocyte senescence in young naive mice in a SMAD2/3-dependent manner. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.

neuroscience↗