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

The 140 amino acid protein alpha-synuclein (alpha S) 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 alpha-helical conformations, but can also act as s seeding event for aggregation and a predominant beta-sheet conformation. In PD patients, alpha S is found to aggregate in various fibrillary structures, and the shift in aggregation and localization is associated with disease progression. Besides full-length alpha S, several related polypeptides are present in neurons. The role of many alpha S-related proteins in the aggregation of alpha S itself is not fully understood Two of these potential aggregation modifiers are the alpha S splicing variant alpha S Delta exon3 (Delta 3) and the paralog beta-synuclein (beta S). 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 alpha S and related proteins. The use of polarized light also revealed the orientation of secondary structure elements. While alpha S led to a destruction of the lipid membrane upon membrane-catalyzed aggregation, beta S and Delta 3 aggregated significantly less, and they did not harm the membrane. Moreover, the latter proteins reduced the membrane damage triggered by alpha S. 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 alpha S-driven membrane damage. The misbalance of alpha S, beta S, and Delta 3 might therefore play a crucial role in neurodegenerative disease.

Automated summary

Alpha-synuclein is a crucial protein in Parkinson's disease, with interactions with membranes leading to aggregation and potential harm to the lipid structure. Other synucleins, such as beta-synuclein and alpha S Delta exon3, play a role in reducing membrane damage caused by alpha-synuclein aggregation. The imbalance of these synucleins may be a significant factor in neurodegenerative diseases.