Biology subjects

Abelein, A.

Publications and source records attributed to Abelein, A..

6 recordsLinked to original sources

bioRxiv2026

Opposing Regulation of Tau Condensation by Phosphorylation Levels and Molecular Chaperone Interactions

Aggregation of the microtubule-stabilizing protein Tau into insoluble deposits is characteristic for several neurodegenerative diseases, including Alzheimer's disease. While phosphorylated Tau (pTau) appears as a normal post-translational modification, the accumulation of hyperphosphorylated Tau aggregates represents a hallmark of these disorders. The molecular mechanisms involved in the conversion from functional Tau into pathological assemblies are still not elucidated. Here, we identified the role of phosphorylation levels on the phase separation and aggregation behavior of Tau, and how these processes can be counteracted by the molecular chaperone-like Bri2 BRICHOS domain. We found that the phosphorylation pattern modulates Tau fibrillation and enhances its droplet-formation propensity. Remarkably, Bri2 BRICHOS generally shifts Tau phase boundaries, counteracting the dense state, and inhibits Tau fibril formation, irrespectively of the degree of phosphorylation. Solution NMR results pinpointed the binding site of Bri2 BRICHOS on pTau, both in the dilute phase and droplet state, revealing an effect on specific regions and phosphorylated residues, which appear to be crucial for the formation and maintenance of the droplet state. Taken together, this study uncovered the opposing regulatory roles of phosphorylation and the anti-amyloid chaperone Bri2 BRICHOS on biomolecular condensation and fibrillation of Tau, providing detailed insights into the molecular mechanisms involved in tauopathies, which may facilitate future treatment strategies using chaperone-based inhibitors.

biophysics↗

bioRxiv2026

Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease

Neurotoxic intermediates formed during amyloid-{beta}(A{beta}) aggregation are thought to drive Alzheimer's disease, yet their rarity and transient nature have obscured their identity and formation pathways in the human brain. Here, we combine super-resolution microscopy and single-molecule functional imaging with kinetic modelling to classify A{beta} intermediates according to their membrane-disrupting activity and connect their damaging effects to the aggregation pathways that generate them. Applying this framework to recombinant A{beta}42, an Alzheimer's knock-in mouse model and human Alzheimer's brain tissue, we find two functionally distinct intermediate populations present across all systems. They form through separate aggregation routes and differ in their neurotoxicity, abundance and susceptibility to inhibition. Both damage neurons and glia, but only one converts into plaques. Suppressing these intermediates pharmacologically in mice reduces plaque burden, attenuates astrogliosis and improves cognition. Our findings connect model systems with human pathology and identify intermediate formation pathways as actionable therapeutic targets across protein-misfolding disorders.

biophysics↗

bioRxiv2026

Single-molecule mass measurements uncover shifting RNA interactions during condensate phase transitions

RNA interactions are a key contributor to the formation and disassembly of intracellular protein condensates. Although some proteins utilize specific RNA-binding domains, these processes can also be mediated by charge interactions with intrinsically disordered regions. Due to the dynamic nature of these systems, investigating the underlying specificity and stoichiometry remains challenging. Here, we demonstrate that single-molecule mass measurements with mass photometry can capture RNA-protein interactions in phase-separated protein systems. Using the approach to investigate RNA-mediated phase shifts of tau condensates, we find that increasing the RNA concentration, which promotes phase re-entry, results in RNA-mediated tau multimerization, where each tau monomer binds a linear RNA sequence of approximately 30 nucleotides. Solution NMR and native mass spectrometry confirm the formation of stable complexes between RNA and the basic proline-rich and repeat domains of tau, which have a net charge of -29. Our findings demonstrate that mass photometry can distinguish between charge neutralization, which drives coacervation, and complex formation, which mediates phase re-entry, making it a highly complementary tool for the study of RNA-mediated phase separation.

biophysics↗

bioRxiv2025

Secondary nucleation of α-Synuclein drives Mitochondria dysfunctions and Lewy body formation in Parkinson's Disease

The seeding of -Synuclein (Syn) is a key driver of Lewy pathology propagation in Parkinsons disease (PD) and forms the basis for recent diagnostic advances. However, it remains unclear how the structural and biochemical features of Syn seeds dictate their propagation efficiency, capacity to induce Lewy body formation, and resulting cellular toxicity. Using genetic and idiopathic PD cell models, we map the pathogenic cascade beginning with the seed-driven conversion of endogenous Syn, followed by impaired degradation, mitochondrial dysfunction, and ultimately Lewy body formation. By coupling kinetic modelling of aggregation with functional readouts, we identify secondary nucleation as the predominant mechanism generating toxic Syn aggregation intermediates, identifying the critical process that links seeding to pathology. Extending this framework to PD brain, we quantitatively correlate seeding capacity with the spatiotemporal spread and severity of Lewy pathology, revealing a mechanistic connection between Syn aggregation dynamics and disease progression at molecular, cellular, and anatomical levels. By unifying molecular mechanism with clinicopathological progression, our work identifies catalytic Syn fibrillar seeds as tractable targets for both disease-modifying therapy and biomarker development in PD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/676873v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@1eca299org.highwire.dtl.DTLVardef@a714d4org.highwire.dtl.DTLVardef@1486db5org.highwire.dtl.DTLVardef@1aa895_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISyn fibril-oligomer interplay drives mitochondrial abnormalities and Lewy pathology C_LIO_LIFibrillar Syn catalyse toxic aggregate formations via secondary nucleation C_LIO_LIPhosphorylated Syn evades lysosomal clearance and drives enhanced dysfunctions C_LIO_LISeeding capacity of Syn predicts Lewy pathology burden and disease progression C_LI

neuroscience↗

bioRxiv2023

Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS

Understanding the molecular mechanisms of neurodegenerative diseases and finding efficient treatments have been major priorities for research and society, yet new therapeutic approaches remain essential to face the socio-economic burden caused by these devastating diseases. Protein misfolding and aggregation are involved in several neurodegenerative disorders, such as -synuclein (Syn) implicated in Parkinsons disease. Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti-amyloid Bri2 BRICHOS domain, can be used to target Syn-associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominately suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), in addition to fibril-end elongation. This mechanism implies a drastic decrease of the oligomer generation rate. Besides targeting secondary nucleation sites on the fibril surface, BRICHOS directly binds to oligomeric Syn species. Further, using ex vivo experiments, BRICHOS effectively diminishes Syn fibril-related toxicity to hippocampal electrophysiology. Our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to Syn neurotoxicity and have the potential as protein-based treatments against neurodegenerative disorders.

biophysics↗

bioRxiv2021

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but the respective mechanisms are not fully understood. The BRICHOS domain constitutes a disease-associated small heat shock protein-like chaperone family, with activities against both amyloid toxicity and amorphous protein aggregation. Here, we show that the activity of two BRICHOS domain families against Alzheimers disease associated amyloid-{beta} neurotoxicity to mouse hippocampi in vitro depends on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The conserved Asp in its ionized state promotes structural flexibility of the BRICHOS domain and has a pKa value between pH 6.0-7.0, suggesting that chaperone effects against amyloid toxicity can be affected by physiological pH variations. Finally, the Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families and animal species, indicating independent evolution of molecular chaperone activities against amyloid fibril formation and non-fibrillar amorphous protein aggregation.

biochemistry↗