Synaptic vesicle mimics affect the aggregation of wild-type and A53T α-synuclein variants differently albeit similar membrane affinity.

Abstract

α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson's disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.

• Authors: Sandra Rocha, Ranjeet Kumar, Istvan Horvath, Pernilla Wittung-Stafshede
• Journal: Protein engineering, design & selection : PEDS (Protein Eng Des Sel) Vol. 32 Issue 2 Pg. 59-66 (12 13 2019) ISSN: 1741-0134 [Electronic] England
• PMID: 31566224 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Mutant Proteins
• Protein Aggregates
• Unilamellar Liposomes
• alpha-Synuclein

Topics

• Cell Membrane (metabolism)
• Mutant Proteins (chemistry, genetics, metabolism)
• Mutation
• Protein Aggregates (drug effects)
• Protein Binding (drug effects)
• Synaptic Vesicles (metabolism)
• Unilamellar Liposomes (pharmacology)
• alpha-Synuclein (chemistry, genetics, metabolism)