title: Analysis of a single α-synuclein fibrillation by the interaction with a protein nanopore.
abstract: The formation of an α-synuclein fibril is critical in the pathogenesis of Parkinson's disease. The native unfolded α-synuclein monomer will translocate through an α-hemolysin nanopore by applied potential at physiological conditions in vitro. Applying a potential transformed α-synuclein into a partially folded intermediate, which was monitored by capture inside the vestibule of an α-hemolysin nanopore with a capture current of 20 ± 1.0 pA. The procedure involves the critical early stage of α-synuclein structural transformation. Further elongation of the intermediate produces a block current to 5 ± 0.5 pA. It is revealed that the early stage fibril of α-synuclein inside the nanopore is affected by intrapeptide electrostatic interaction. In addition, trehalose cleared the fibrillation by changing the surface hydrophobic interaction of A53T α-synuclein, which did not show any inhibition effect from WT α-synuclein. The results proved that the interpeptide hydrophobic interactions in the elongation of A53T α-synuclein protofilaments can be greatly weakened by trehalose. This suggests that trehalose inhibits the interpeptide interaction involved in protein secondary structure. The hydrophobic and electrostatic interactions are associated with an increase in α-synuclein fibrillation propensity. This work provides unique insights into the earliest steps of the α-synuclein aggregation pathway and provides the potential basis for the development of drugs that can prevent α-synuclein aggregation at the initial stage.
authors.affiliation: Shanghai Key Laboratory of Functional Materials Chemistry and Department of Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gu
authors.forename: Chan
authors.initials: C
authors.lastname: Cao
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Long
mesh_terms: D000595:Amino Acid Sequence; D008969:Molecular Sequence Data; D058608:Nanopores; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D051844:alpha-Synuclein / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein