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Title: α-Synuclein amyloid fibrils with two entwined, asymmetrically associated protofibrils [α-Synuclein amyloid fibrils with two entwined, asymmetrically associated, protofibrils and axially stacked metal binding sites]

Parkinson disease and other progressive neurodegenerative conditions are characterized by the intracerebral presence of Lewy bodies, containing amyloid fibrils of α-synuclein. We used cryo-electron microscopy and scanning transmission electron microscopy (STEM) to study in vitro-assembled fibrils. These fibrils are highly polymorphic. Focusing on twisting fibrils with an inter-crossover spacing of 77 nm, our reconstructions showed them to consist of paired protofibrils. STEM mass per length data gave one subunit per 0.47 nm axial rise per protofibril, consistent with a superpleated β-structure. The STEM images show two thread-like densities running along each of these fibrils, which we interpret as ladders of metal ions. These threads confirmed the two-protofibril architecture of the 77-nm twisting fibrils and allowed us to identify this morphotype in STEM micrographs. Some other, but not all, fibril morphotypes also exhibit dense threads, implying that they also present a putative metal binding site. As a result, we propose a molecular model for the protofibril and suggest that polymorphic variant fibrils have different numbers of protofibrils that are associated differently.
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [5] ;  [1]
  1. National Institutes of Health, Bethesda, MD (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
  3. Univ. of Montpellier, Montpellier (France); Univ. ITMO, St. Petersburg (Russia)
  4. Univ. of Southern California, Los Angeles, CA (United States); Karunya Univ., Tamil Nadu (India)
  5. Univ. of Southern California, Los Angeles, CA (United States)
Publication Date:
Report Number(s):
Journal ID: ISSN 0021-9258
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 291; Journal Issue: 5; Journal ID: ISSN 0021-9258
American Society for Biochemistry and Molecular Biology
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; amyloid; cryo-electron microscopy; fibril; metalloprotein; microscopic imaging; microscopy; cross-β structure; molecular mass measurements; scanning transmission electron microscopy; superpleated β structure
OSTI Identifier: