title: Structural basis for the dissociation of α-synuclein fibrils triggered by pressure perturbation of the hydrophobic core.
abstract: Parkinson's disease is a neurological disease in which aggregated forms of the α-synuclein (α-syn) protein are found. We used high hydrostatic pressure (HHP) coupled with NMR spectroscopy to study the dissociation of α-syn fibril into monomers and evaluate their structural and dynamic properties. Different dynamic properties in the non-amyloid-β component (NAC), which constitutes the Greek-key hydrophobic core, and in the acidic C-terminal region of the protein were identified by HHP NMR spectroscopy. In addition, solid-state NMR revealed subtle differences in the HHP-disturbed fibril core, providing clues to how these species contribute to seeding α-syn aggregation. These findings show how pressure can populate so far undetected α-syn species, and they lay out a roadmap for fibril dissociation via pathways not previously observed using other approaches. Pressure perturbs the cavity-prone hydrophobic core of the fibrils by pushing water inward, thereby inducing the dissociation into monomers. Our study offers the molecular details of how hydrophobic interaction and the formation of water-excluded cavities jointly contribute to the assembly and stabilization of the fibrils. Understanding the molecular forces behind the formation of pathogenic fibrils uncovered by pressure perturbation will aid in the development of new therapeutics against Parkinson's disease.
authors.affiliation: Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Guilherme A P
authors.initials: GA
authors.lastname: de Oliveira
authors.affiliation: Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Mayra de A
authors.initials: MA
authors.lastname: Marques
authors.affiliation: Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Cruzeiro-Silva
authors.affiliation: Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Yraima
authors.initials: Y
authors.lastname: Cordeiro
authors.affiliation: Department of Chemistry and Chemical Biology, Physical Chemistry, Technische Universität Dortmund, Dortmund, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schuabb
authors.affiliation: Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.|Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Brazil.
authors.forename: Adolfo H
authors.initials: AH
authors.lastname: Moraes
authors.affiliation: Department of Chemistry and Chemical Biology, Physical Chemistry, Technische Universität Dortmund, Dortmund, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Winter
authors.affiliation: Department of Structural Biology, Leibniz Institute für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Oschkinat
authors.affiliation: Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Debora
authors.initials: D
authors.lastname: Foguel
authors.affiliation: Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Mônica S
authors.initials: MS
authors.lastname: Freitas
authors.affiliation: Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Jerson L
authors.initials: JL
authors.lastname: Silva
mesh_terms: D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006874:Hydrostatic Pressure; D019906:Nuclear Magnetic Resonance, Biomolecular; D066329:Protein Aggregates; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D066329:Protein Aggregates; C497604:SNCA protein, human; D051844:alpha-Synuclein