Abstract
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 models of β-helical pore assemblies are consistent with α-synucleinA53T transfected rat immunofluorescence epitope maps. Atomic force microscopy reveals that α-synuclein peptides aggregate into anisotropic fibrils lacking the density or circumference of a steric-zipper. Moreover, fibrillation was blocked by mutations designed to hinder β-helical but not steric-zipper conformations. β-helical species provide a structural basis for previously described biophysical properties that are incompatible with a steric-zipper, provide pathogenic mechanisms for familial human α-synuclein mutations, and offer a direct cytotoxic target for therapeutic development.
Highlights
A-Synuclein aggregation is a pathological hallmark of both familial and idiopathic Parkinson’s disease (PD).[1,2] Predating aSyn genetic characterization, the protein was known as the Non-Amyloid-Component (NAC) of Lewy bodies, an acronym still used to describe the central aggregation-prone domain of aSyn
We describe a b-helical homology model of a-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
Atomic force microscopy reveals that a-synuclein peptides aggregate into anisotropic fibrils lacking the density or circumference of a steric-zipper
Summary
A-Synuclein (aSyn) aggregation is a pathological hallmark of both familial and idiopathic Parkinson’s disease (PD).[1,2] Predating aSyn genetic characterization, the protein was known as the Non-Amyloid-Component (NAC) of Lewy bodies, an acronym still used to describe the central aggregation-prone domain of aSyn. In PD, aSyn aggregates into higher-order species including dimers, annular pores, and fibers These pathogenic conformations play pivotal roles in PD initiation, neurotoxicity, and transcellular propagation. DsRibbons appear to be significantly more robust and do not degrade to seed cylinders.[13] dsRibbons routinely present in EM as two $4 Â 5.5 nm strands separated by $1.4 nm[14] and in AFM as 5.2–6.6 nm high ribbons.[15,16] Such an $1.4 nm gap is not observed for cylindrical protofilament dimers. We present models in which the dsRibbons exist in equilibrium with other pathological conformations, which are distinct from the denser GK cylinder These models were designed to provide rationale for clinical and biophysical observations and may be of use to guide ab initio model design for high-resolution experimental data and to design disease-modifying therapeutics. GK is incredibly rigid: GK is and can only adopt flat to RHH conformations with a much larger pitch than that has been observed for dsRibbons [Figs. 1(b) and 2 (Multimedia view)]. b-sheets comprised of non-glycine L-amino acids are inherently right-handed due primarily to intrasheet O/Cb steric clashes.[24]
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