Equilibrium among Type 2 oligomers, protofibrils, and fibrils.
Numerous studies indicate that α-Syn oligomers and fibrils exist in a
dynamic equilibrium. An overview of our working hypotheses for this
equilibrium among Type 2 oligomers and fibrils is given in Fig. 17. The
oligomers of Fig. 4 with diameters consistent with our tetramer models
tend to aggregate in strings. Antiparallel pairs of Sy5 β-strands
comprise the longest and most hydrophobic regions on the exterior Type
2A tetramers; thus, they form the most probable regions of interactions
between Type 2A tetramers (green strands in top left of Fig. 17).
Portions of two Sy5 strands related by 2-fold symmetry pack tightly in
some fibril structures [7,8,10] and most mutations leading to
early-onset PD occur in Sy5. Thus it is plausible that interactions
between Sy5 segments are vital to formation of functional α-Syn
assemblies and that disruptions of these interactions favor formation of
toxic assemblies. In contrast, antiparallel pairs of Sy8 strands of the
NAC domains form the longest and most hydrophobic regions on the
exterior of Type 2P tetramers (blue strands in Fig 17). Interactions of
these segments occur at regions of 2-fold symmetry in Twister type
fibrils [8]. Type 2P tetramers could be favored when concentrations
are sufficiently high for most tetramers to form strings or clusters
that bury the NAC segments. Additional monomers may bind to tetramers to
form hexamers. Likewise, tetramers and hexamers may merge to form larger
assemblies such as octamers proposed for lipoproteins and octamers,
decamers, and dodecamers proposed for annular protofibrils and Fe
II-O2 induced oligomers. Annular protofibrils may then
interact to form tubular protofibrils, which slowly morph into fibrils.
But interactions are not unidirectional; under some conditions fibrils
can decompose to form oligomers that become smaller with time [2].