title: Nuclear localization of alpha-synuclein and its interaction with histones.
abstract: The aggregation of alpha-synuclein is believed to play an important role in the pathogenesis of Parkinson's disease as well as other neurodegenerative disorders ("synucleinopathies"). However, the function of alpha-synuclein under physiologic and pathological conditions is unknown, and the mechanism of alpha-synuclein aggregation is not well understood. Here we show that alpha-synuclein forms a tight 2:1 complex with histones and that the fibrillation rate of alpha-synuclein is dramatically accelerated in the presence of histones in vitro. We also describe the presence of alpha-synuclein and its co-localization with histones in the nuclei of nigral neurons from mice exposed to a toxic insult (i.e., injections of the herbicide paraquat). These observations indicate that translocation into the nucleus and binding with histones represent potential mechanisms underlying alpha-synuclein pathophysiology.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
authors.forename: John
authors.initials: J
authors.lastname: Goers
authors.forename: Amy B
authors.initials: AB
authors.lastname: Manning-Bog
authors.forename: Alison L
authors.initials: AL
authors.lastname: McCormack
authors.forename: Ian S
authors.initials: IS
authors.lastname: Millett
authors.forename: Sebastian
authors.initials: S
authors.lastname: Doniach
authors.forename: Donato A
authors.initials: DA
authors.lastname: Di Monte
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Fink
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism*; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D010269:Paraquat / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D006657:Histones; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D010269:Paraquat