Type 1 α-Syn Models: A Possible Toxic Pathway
Identification of which synuclein assemblies are essential and which are
toxic may be vital for development of treatments. It is well established
that an α-helical form of α-Syn binds to membrane surfaces and plays a
vital role in the fusion of synaptic vesicles with the plasma membrane.
However, interactions of α-Syn oligomers with membranes are not that
simple: α-Syn adopts a multitude of membrane-bound conformations in
unroofed cells and the Ct domain participates in membrane localization
[61]. Using a microfluid setup that recapitulated the composition of
the plasma membrane, Heo and Pinchet [23] found that α-Syn induced
pores of discrete sizes and immobilized lipids on both the cis and trans
sides of the membrane, indicating deep penetration inside the membrane.
Quist et al. [21] used both electrical recording of membrane
currents and atomic force microscopy to show that numerous amyloids,
including α-Syn and its NAC domain, can form ion channels of multiple
sizes in membranes. Kim et al. [22] also found that α-Syn oligomers
formed well-defined conductance states in a variety of membranes and
that the beta-structure of these membrane-bound oligomers differed from
that of α-Syn fibrils. Parres-Gold et al. [24] used scanning ion
conductance microscopy (SICM) to show that α-Syn oligomers induce
morphological changes and formation of large transient pores in live
SH-SY5Y neuroblastoma cells. Toxic α-Syn accumulation in SH-SY5Y is
alleviated by membrane depolarization
[62], suggesting that membrane
interactions of α-Syn are related to toxicity in these cells. These
interactions are affected by the lipid composition of the membranes.
Binding of ganglioside and cholesterol appear to be involved in
penetration of the membrane by α-Syn [26]. Based on results of
nuclear magnet resonance spectroscopy
Man et al. [63] concluded that
cholesterol reduces the local affinity of the NAC domain to synaptic
vesicles, supporting the role of disorder-to-order equilibrium of the
NAC region. However, cholesterol-containing lipid nanodiscs accelerates
oligomerization of α-Syn [64].
When the nanodiscs are made of DOPC, interaction of the NAC domain with
the bilayer is increased; but when DOPC, DOPE, and DOPG all comprise the
nanodiscs, binding of the NAC domain is not affected while binding of
the Nt and Ct domains are inhibited.
Penetration of the alkyl phase of the membrane appears to depend upon
the conformation of the α-Syn oligomer. Fusco et al. [65] analyzed
two types of α-Syn oligomers of similar size that they called A and B.
Type A interacts only with the surfaces of membranes, has little rigid
secondary structure, and is not toxic. In contrast, segment 70-88 (red
background in Figs. 18d and 19b) of the toxic Type B has a rigid
β-secondary that penetrates the alkyl phase of the membrane. Most of
this region is formed by Sy7 which is deleted in non-toxic β-Syn. Our
working hypothesis is that their Type B oligomer is a Type 1 trimer in
which the NAC domain forms a core six-stranded antiparallel β-barrel
with the Sy7 segment in the turn region of the β-hairpin exposed.