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

Abstract

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.

Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

“…Alpha-synuclein modulates the release of neurotransmitters from presynaptic terminals by binding and clustering synaptic vesicles and chaperoning the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to the protein synaptobrevin-2 (VAMP2) [ 28 , 29 ] whereas beta-synuclein and gamma-synuclein modulate the synaptic vesicular binding of alpha-synuclein and thus reduce the synaptic physiological activity of alpha-synuclein [ 30 , 31 ] ( Table 1 ). Moreover, in vitro and in vivo experiments have revealed that all three members of the synuclein family have chaperone activity [ 32 , 33 , 34 ].…”