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Fig. 3 | Molecular Neurodegeneration

Fig. 3

From: Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles

Fig. 3

CryoEM structures of four distinct types of full length αS fibril. The four structures are known as type 1a ‘rod’ [25, 26], type 1b ‘twister’ [27], type 2a and type 2b polymorphs [53]. Single layer density slices within the rod structure have revealed a Greek Key topology with rotational symmetry about the axis of the fibril. In contrast, single layers within the twister structure reveal a β-arch motif. Both type 1 polymorphs contain two protofilaments composed of stacked β-sheets with rotational symmetry about the fibril axis. In contrast, type 2 polymorphs lack the steric zipper geometry identified in type 1 polymorphs and are instead characterised by a hydrophobic cleft that is stabilised by intermolecular salt bridges and additional interactions between the NAC and the N-terminus. Left Box) Shown is the 3D model of the type 1a (rod) and type 1b (twister) fibril polymorphs, respectively, with their distinctively different helical pitches depicted. Top) Shown are representative regions of density maps of both polymorphs are superimposed with their models showing match of side chains with cryoEM densities. Bottom) How a 5 nm protofilament [24] may represent a shared fibril kernel from which both rod and twister fibrils can develop. In rod fibrils the interface is composed of residues within the preNAC region (blue, residues 47–56), an area in which most of the early onset PD mutations are located (cyan). In the twister fibrils the interface is composed of residues within the NAC core region (red, residues 68–78). This suggests that early onset mutations disfavour the rod like fibrils over the twister structures, offering the possibility for fibril morphogenesis and the potential to shift the aS population towards a more toxic polymorph. The left hand panel has been adapted from Li et al. 2018 [27] (CC-BY 4.0). The right hand panels are adapted from Guerrero-Ferreira et al 2019 [53] (CC-BY-NC-ND 4.0) and show schematic representations of all four currently characterized αS polymorphs with the with the N-terminus in blue, the NAC region in red and the C-terminus in yellow

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