Aggregated alpha-synuclein fibrils (site-9 pocket) (aSyn fibrils (site-9))

Aggregated alpha-synuclein fibrils are the pathological hallmark of synucleinopathies, including Parkinson's disease (PD) and Multiple System Atrophy (MSA). These fibrils are composed of misfolded alpha-synuclein proteins that adopt a cross-beta sheet structure, which is highly stable and neurotoxic (Schweighauser et al., Nature 2020). The site-9 pocket is a specific, high-affinity binding site identified within the structural architecture of these fibrils, particularly in the polymorphs associated with MSA. This pocket is formed by the packing of the non-amyloid component (NAC) region and is a primary target for the development of selective positron emission tomography (PET) tracers like ACI-12589 (Kuebler et al., JNM 2023). By binding to this site, diagnostic agents can distinguish alpha-synuclein aggregates from other amyloidogenic proteins such as tau or amyloid-beta. Furthermore, the site-9 pocket is a focal point for therapeutic strategies aimed at small-molecule inhibition of fibril elongation and seeding, which are key drivers of disease progression in the central nervous system (Smith et al., Nat Rev Drug Discov 2023).

Other names

Alpha-synuclein aggregatesSNCA fibrilsLewy body filamentsSite 9 binding sitePathological alpha-synuclein filamentsMSA-type alpha-synuclein filaments

High-affinity binding to the site-9 hydrophobic pocket of alpha-synuclein fibrils to facilitate PET imaging or sterically inhibit the recruitment of monomers to the fibril ends.