Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: implications for y-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 α-synuclein. Early- onset PD has been linked to two point mutations in the gene that encodes α-synuclein. suggesting that disease may arise from ac- celerated fibrillization. However, the identity of the pathogenic species and.its relationship to the α-synuclein fibril has not been eIucidated. In this in vitro study, the rates of disappearance of monomeric alfa-synuclein and appearance of fibrillar o-synuclein were compared for the wild-type (WT and two mutant proteins. as well as equimolar mixtures that may model the heterozygous PD patients. Whereas one of the mutant proteins (A53T) and an equimoIar mixture of A53T and WT fibrillized more rapidly than WT a-synuclein, the other (A30P) and the corresponding equimolar mixture with WT fibrillized more slowly. However, under condi- tions that ultimately produced fibrils. the A30P monomer was consumed at a comparable rate or slightly more rapidly than the WT monomer, whereas A53T was consumed even more rapidly. The difference between these trends suggested the existence of nonfibrillar α-synuclein oligomers, some of which were separated from fibrillar and monomeric alfa-synuclein by sedimentation fol- Iowed by gel-f iltration chromatography. Spheres (range of heights: 2-6 nm), chains of spheres (protofibrils), and rings resem- bIing circularized protofibrils (height: ca. 4 nm) were distinguished from fibriIs (height: ca. 8 nm) by atomic force microscopy. lmpor- tantly. drug candidates that inhibit α-synuclein fibrillization but do not block its oligomerization could mimic the A30P mutation and thus may accelerate disease progression.