Synuclein Family Members Prevent Membrane Damage by Counteracting α-Synuclein Aggregation

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2021
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The 140 amino acid protein α-synuclein (αS) is an intrinsically disordered protein (IDP) with various roles and locations in healthy neurons that plays a key role in Parkinson’s disease (PD). Contact with biomembranes can lead to α-helical conformations, but can also act as s seeding event for aggregation and a predominant β-sheet conformation. In PD patients, αS is found to aggregate in various fibrillary structures, and the shift in aggregation and localization is associated with disease progression. Besides full-length αS, several related polypeptides are present in neurons. The role of many αS-related proteins in the aggregation of αS itself is not fully understood Two of these potential aggregation modifiers are the αS splicing variant αS Δexon3 (Δ3) and the paralog β-synuclein (βS). Here, polarized ATR-FTIR spectroscopy was used to study the membrane interaction of these proteins individually and in various combinations. The method allowed a continuous monitoring of both the lipid structure of biomimetic membranes and the aggregation state of αS and related proteins. The use of polarized light also revealed the orientation of secondary structure elements. While αS led to a destruction of the lipid membrane upon membrane-catalyzed aggregation, βS and Δ3 aggregated significantly less, and they did not harm the membrane. Moreover, the latter proteins reduced the membrane damage triggered by αS. There were no major differences in the membrane interaction for the different synuclein variants. In combination, these observations suggest that the formation of particular protein aggregates is the major driving force for αS-driven membrane damage. The misbalance of αS, βS, and Δ3 might therefore play a crucial role in neurodegenerative disease.

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570 Biowissenschaften, Biologie
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polarized ATR-FTIR; protein–membrane interaction; protein–protein interaction; alpha-synuclein; beta-synuclein
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ISO 690SCHEIBE, Christian, Christiaan KARREMAN, Stefan SCHILDKNECHT, Marcel LEIST, Karin HAUSER, 2021. Synuclein Family Members Prevent Membrane Damage by Counteracting α-Synuclein Aggregation. In: Biomolecules. MDPI. 2021, 11(8), 1067. eISSN 2218-273X. Available under: doi: 10.3390/biom11081067
BibTex
@article{Scheibe2021-08Synuc-54475,
  year={2021},
  doi={10.3390/biom11081067},
  title={Synuclein Family Members Prevent Membrane Damage by Counteracting α-Synuclein Aggregation},
  number={8},
  volume={11},
  journal={Biomolecules},
  author={Scheibe, Christian and Karreman, Christiaan and Schildknecht, Stefan and Leist, Marcel and Hauser, Karin},
  note={Article Number: 1067}
}
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