title: Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation.
abstract: β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson's disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant αS tetramers. The PD-causing mutation A53T decreases tetramers in mouse brain. Neurons derived from an A53T patient have decreased tetramers. Neurons expressing E46K do also, and adding 1-2 E46K-like mutations into the canonical αS repeat motifs (KTKEGV) further reduces tetramers, decreases αS solubility and induces neurotoxicity and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by PD-causing missense mutations and the neurotoxicity and inclusions induced by markedly decreasing tetramers suggest that decreased α-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dettmer
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Newman
authors.affiliation: The Whitehead Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Soldner
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Luth
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nora C
authors.initials: NC
authors.lastname: Kim
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: von Saucken
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Sanderson
authors.affiliation: 1] The Whitehead Institute, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Bartels
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Selkoe
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells; D051379:Mice; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497604:SNCA protein, human; C497605:Snca protein, mouse; C497606:Snca protein, rat; D051844:alpha-Synuclein