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[Preprint]. 2024 Aug 18:2024.07.28.605529. Originally published 2024 Jul 29. [Version 2] doi: 10.1101/2024.07.28.605529

Live-Cell Quantification Reveals Viscoelastic Regulation of Synapsin Condensates by α-Synuclein

Huan Wang, Christian Hoffmann, Johannes V Tromm, Xiao Su, Jordan Elliott, Han Wang, Jean Baum, Zhiping P Pang, Dragomir Milovanovic, Zheng Shi
PMCID: PMC11361170  PMID: 39211102

Abstract

Synapsin and α-synuclein represent a growing list of condensate-forming proteins where the material states of condensates are directly linked to cellular functions (e.g., neurotransmission) and pathology (e.g., neurodegeneration). However, quantifying condensate material properties in living systems has been a significant challenge. To address this, we develop MAPAC (micropipette aspiration and whole-cell patch clamp), a platform that allows direct material quantification of condensates in live cells. We find 10,000-fold variations in the viscoelasticity of synapsin condensates, regulated by the partitioning of α-synuclein, a marker for synucleinopathies. Through in vitro reconstitutions, we identify 4 molecular factors that distinctly regulate the viscosity and interfacial tension of synapsin condensates, verifying the cellular effects of α-synuclein. Overall, our study provides unprecedented quantitative insights into the material properties of neuronal condensates and reveals a crucial role of α-synuclein in regulating condensate viscoelasticity. Furthermore, we envision MAPAC applicable to study a broad range of condensates in vivo.  

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