Abstract
Liquid‐liquid phase separation (LLPS) has emerged as a key mechanism for intracellular organization, and many recent studies have provided important insights into the role of LLPS in cell biology. There is also evidence that LLPS is associated with a variety of medical conditions, including neurodegenerative disorders. Pathological aggregation of α‐synuclein, which is causally linked to Parkinson's disease, can proceed via droplet condensation, which then gradually transitions to the amyloid state. We show that the antimicrobial peptide LL‐III is able to interact with both monomers and condensates of α‐synuclein, leading to stabilization of the droplet and preventing conversion to the fibrillar state. The anti‐aggregation activity of LL‐III was also confirmed in a cellular model. We anticipate that studying the interaction of antimicrobial‐type peptides with liquid condensates such as α‐synuclein will contribute to the understanding of disease mechanisms (that arise in such condensates) and may also open up exciting new avenues for intervention.
Highlights
Introduction αSynuclein (α-Syn) is a small intrinsically disordered presynaptic protein which regulates neurotransmitter vesicle cycling
By means of circular dichroism (CD) spectroscopy, we explored the effect of Liquid-liquid phase separation (LLPS) formation and LL-III partitioning on the conformation of the protein
Even after 10 days, the CD-spectrum of the LL-III/α-Syn mixture showed only features of a random conformation, i. e., at a time point where droplets had formed. This indicates that no significant conformational changes occurred upon formation of the droplet phase, highlighting the stability of the co-condensate formed by α-Syn and LL-III
Summary
Introduction αSynuclein (α-Syn) is a small intrinsically disordered presynaptic protein which regulates neurotransmitter vesicle cycling. Some droplets were still visible (Figure S1, D), supporting the previous observation that the transition from the monomeric to the fibrillar state occurs through the formation of α-Syn condensates.[8]
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