Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: Implications for pathogenesis and therapy

摘要: The Parkinson's disease (PD) substantia nigra is characterized by the presence of Lewy bodies containing fibrillar alpha-synuclein. Early-onset PD has been linked to two point mutations in gene that encodes alpha-synuclein, suggesting may arise from accelerated fibrillization. However, identity pathogenic species and its relationship alpha-synuclein fibril not elucidated. In this vitro study, rates disappearance monomeric appearance were compared for wild-type (WT) mutant proteins, as well equimolar mixtures model heterozygous patients. Whereas one proteins (A53T) an mixture A53T WT fibrillized more rapidly than other (A30P) corresponding with slowly. under conditions ultimately produced fibrils, A30P monomer was consumed at a comparable rate or slightly monomer, whereas even rapidly. difference between these trends suggested existence nonfibrillar oligomers, some which separated sedimentation followed gel-filtration chromatography. Spheres (range heights: 2-6 nm), chains spheres (protofibrils), rings resembling circularized protofibrils (height: ca. 4 nm) distinguished fibrils 8 atomic force microscopy. Importantly, drug candidates inhibit fibrillization but do block oligomerization could mimic mutation thus accelerate progression.