Ewa Andrzejewska

Nov 20, 2024 | nature.com | Dhiman Ghosh |Matthias Schneider |Dzmitry Ashkinadze |Harindranath Kadavath |Peter Güntert |Georg Krainer | +4 more

AbstractThe complex kinetics of disease-related amyloid aggregation of proteins such as α-Synuclein (α-Syn) in Parkinson’s disease and Aβ42 in Alzheimer’s disease include primary nucleation, amyloid fibril elongation and secondary nucleation. The latter can be a key accelerator of the aggregation process. It has been demonstrated that the chaperone domain BRICHOS can interfere with the secondary nucleation process of Aβ42.

Aug 17, 2024 | nature.com | Catherine Xu |Georg Meisl |Ewa Andrzejewska |Georg Krainer |Irina Edu |Michele Vendruscolo | +1 more

AbstractOligomeric species arising during the aggregation of α-synuclein are implicated as a major source of toxicity in Parkinson’s disease, and thus a major potential drug target. However, both their mechanism of formation and role in aggregation are largely unresolved. Here we show that, at physiological pH and in the absence of lipid membranes, α-synuclein aggregates form by secondary nucleation, rather than simple primary nucleation, and that this process is enhanced by agitation.

Apr 16, 2024 | nature.com | Robert Horne |Ewa Andrzejewska |Pietro Sormanni |Byron Caughey

AbstractMachine learning methods hold the promise to reduce the costs and the failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where the development of disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine learning approach to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson’s disease and other synucleinopathies.

Mar 18, 2024 | nature.com | Danny D. Sahtoe |Ewa Andrzejewska |Hannah Han |Matthias Schneider |Georg Meisl |Hannah Nguyen | +2 more

AbstractSegments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach to bind such segments in β-strand and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs bind their cognate peptides in vitro with nanomolar affinities.

Jun 21, 2023 | biorxiv.org | Byron Caughey |Robert Horne |Ewa Andrzejewska |Parvez Alam

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