High-resolution structural information of membrane-bound α-synuclein provides insight into the MoA of the anti-Parkinson drug UCB0599

Significance Although the pathophysiological relevance of α-synuclein in Parkinson’s disease (PD) is clearly established, its natural function and the mechanism by which it causes toxicity are not fully understood. Recruitment of α-synuclein to membranes is required for correct vesicle dynamics, while altered oligomerization at membranes can contribute to PD. We present a high-resolution structural model of α-synuclein in its oligomeric, membrane-bound state based on solution NMR and chemical cross-linking mass spectrometry (XL-MS) restraints. The obtained structures prove useful in explaining the consequences of well-known familial PD mutations and revealed a plausible mode-of-action for UCB0599, a drug designed to interfere with membrane-bound α-synuclein showing disease-modifying potential. We expect this structural information to support future research furthering our understanding of α-synuclein’s intricate functions.

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