Figure 1.

Preparation and application of α-synuclein preformed fibrils to reconstruct multiple steps of Lewy body formation and pathological protein transmission.

(A) Major steps in PFF-induced αSyn aggregation model: (1) formation of αSyn fibrils in vitro; (2) cellular uptake of αSyn PFFs; (3) processing and release to cytoplasm; (4) recruitment of endogenous αSyn; (5) seeding of endogenous αSyn misfolding, formation of oligomers and insoluble αSyn fibrils; (6) maturation of fibrils and formation of Levy Bodies containing fragment of lipid membranes and mitochondria; (7) lysosomal and proteasomal degradation of misfolded αSyn oligomers and fibrils; (8) release and propagation of misfolded αSyn. (B) Application of αSyn PFFs and genetic models to study molecular mechanisms and develop therapies targeting pathological αSyn aggregation, and the remaining questions. Numbers correspond to major PFF-induced αSyn aggregation steps depicted in Figure 1. ASOs: Anti-sense oligonucleotides; HMW: high molecular weight; KO: knockout; LBs: Lewy bodies; NTFs: neurothrophic factors; OE: overexpression; PROTACs: proteolysis targeting chimeras.