Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding Article Swipe

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Fibril Mutant Neuropathology Amyloid (mycology) Wild type In vivo Biophysics Chemistry Mutation Point mutation Biology Strain (injury) Biochemistry Genetics Anatomy Pathology Gene Medicine Disease Inorganic chemistry

Houfang Long , Wenxi Zheng , Yang Liu , Yunpeng Sun , Kun Zhao , Zhenying Liu , Wencheng Xia , Shiran Lv , Zhengtao Liu , Dan Li , Kaiwen He , Cong Liu ·

YOU? · · 2021 · Open Access · · DOI: https://doi.org/10.1073/pnas.2012435118 · OA: W3161372171

Significance Amyloid deposition of α-syn is a hallmark of PD. Heterozygous point mutations of α-syn are associated with the early-onset and rapid progression of fPD. In this study, we found the fibril strain formed by a familial mutant hE46K induced early-onset motor deficit and enhanced α-syn aggregation in vivo. More importantly, we showed through cryogenic electron microscopy and in vivo studies the E46K fibril strain can template wild-type α-syn monomer to form amyloid fibrils, which inherit both the structure and propagation potency of the template. Our work reveals the structural basis underlying the cross-seeding between wild-type and mutant α-syn, underscores the importance of fibril structure in determining α-syn neuropathology, and provides mechanistic understanding of the pathology of E46K-associated fPD.