The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein
| Autor: | Dan Li, Qin Cao, Bo Sun, Houfang Long, Cong Liu, Bin Dai, Kun Wang, Yaoyang Zhang, Wencheng Xia, Yunpeng Sun, Xia Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
Amyloid
Science animal diseases Mutant General Physics and Astronomy macromolecular substances Microscopy Atomic Force medicine.disease_cause Fibril environment and public health Article General Biochemistry Genetics and Molecular Biology Cell Line law.invention Rats Sprague-Dawley law medicine Animals Humans Neurons Synucleinopathies Mutation Intrinsically disordered proteins Multidisciplinary Strain (chemistry) Chemistry Cryoelectron Microscopy Wild type General Chemistry In vitro nervous system diseases nervous system alpha-Synuclein Biophysics Electron microscope Structural biology |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-10 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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). G51D mutation of α-synuclein (α-syn) causes a subset of familial Parkinson’s disease that is characterized by an early onset and rapid progression of the disease. Here, the authors present the cryo-EM structure of full-length G51D α-syn fibrils that is distinct from other known α-syn fibril structures, and they show that G51D fibrils can cross-seed wild-type (WT) α-syn and that these cross-seeded WT fibrils replicate the G51D fibril structure. |
| Databáze: | OpenAIRE |
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