Abstract
α-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. How different α-syn fibril strains are produced and selected under disease conditions remains poorly understood. In this study, we show that the hereditary mutation G51D induces α-syn to form a distinct fibril strain in vitro. The cryogenic electron microscopy (cryo-EM) structure of the G51D fibril strain was determined at 2.96 Å resolution. The G51D fibril displays a relatively small and extended serpentine fold distinct from other α-syn fibril structures. Moreover, we show by cryo-EM that wild-type (WT) α-syn can assembly into the G51D fibril strain via cross-seeding with G51D fibrils. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson’s disease (fPD).
Highlights
Α-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies
By performing the Thioflavin T (ThT) kinetic assay and negativestaining transmission electron microscopy (NS-TEM), we showed that G51D α-syn spontaneously forms long and unbranched amyloid fibrils with a lag time of ~16 h in 50 mM phosphate buffer, pH 7.0, 50 mM NaCl (Fig. 1a)
Different fibril polymorphs exhibit distinct physiochemical and pathological properties, which are believed to underlie the clinicopathological variability of the associated diseases[17,19,37,38,39]
Summary
Α-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson’s disease (fPD). 1234567890():,; Recent cryo-EM studies have shown that hereditary mutations (e.g., H50Q, E46K, and A53T) and disease-associated phosphorylation (pY39) of α-syn can induce distinct fibril strains[22,23,24,25,26]. This implies that mutation and post-translational modification (PTM) may play important roles in α-syn strain selection. Our work demonstrates that the G51D α-syn fibril structure presented here can be adopted by both G51D and WT α-syn, which indicates that the mutant and WT α-syn may concertedly accelerate the disease progression in fPD with G51D mutation
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