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Non-steric-zipper models for pathogenic ?-synuclein conformers.

ABSTRACT: Parkinson's disease neurodegenerative brain tissue exhibits two biophysically distinct ?-synuclein fiber isoforms-single stranded fibers that appear to be steric-zippers and double-stranded fibers with an undetermined structure. Herein, we describe a ?-helical homology model of ?-synuclein that exhibits stability in probabilistic and Monte Carlo simulations as a candidate for stable prional dimer conformers in equilibrium with double-stranded fibers and cytotoxic pore assemblies. Molecular models of ?-helical pore assemblies are consistent with ?-synucleinA53T transfected rat immunofluorescence epitope maps. Atomic force microscopy reveals that ?-synuclein peptides aggregate into anisotropic fibrils lacking the density or circumference of a steric-zipper. Moreover, fibrillation was blocked by mutations designed to hinder ?-helical but not steric-zipper conformations. ?-helical species provide a structural basis for previously described biophysical properties that are incompatible with a steric-zipper, provide pathogenic mechanisms for familial human ?-synuclein mutations, and offer a direct cytotoxic target for therapeutic development.

SUBMITTER: Schuman B 

PROVIDER: S-EPMC6481714 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Non-steric-zipper models for pathogenic α-synuclein conformers.

Schuman Brock B   Won Amy A   Brand-Arzamendi Koroboshka K   Koprich James B JB   Wen Xiao-Yan XY   Howson Patrick A PA   Brotchie Jonathan M JM   Yip Christopher M CM  

APL bioengineering 20180501 2

Parkinson's disease neurodegenerative brain tissue exhibits two biophysically distinct α-synuclein fiber isoforms-single stranded fibers that appear to be steric-zippers and double-stranded fibers with an undetermined structure. Herein, we describe a β-helical homology model of α-synuclein that exhibits stability in probabilistic and Monte Carlo simulations as a candidate for stable prional dimer conformers in equilibrium with double-stranded fibers and cytotoxic pore assemblies. Molecular model  ...[more]

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