title: Subcellular Parkinson's Disease-Specific Alpha-Synuclein Species Show Altered Behavior in Neurodegeneration.
abstract: Parkinson's disease and other synucleinopathies are characterized by the presence of intra-neuronal protein aggregates enriched in the presynaptic protein α-synuclein. α-synuclein is considered an intrinsically disordered 14 kDa monomer, and although poorly understood, its transition to higher-order multimeric species may play central roles in healthy neurons and during Parkinson's disease pathogenesis. In this study, we demonstrate that α-synuclein exists as defined, subcellular-specific species that change characteristics in response to oxidative stress in neuroblastoma cells and in response to Parkinson's disease pathogenesis in human cerebellum and frontal cortex. We further show that the phosphorylation patterns of different α-synuclein species are subcellular specific and dependent on the oxidative environment. Using high-performance liquid chromatography and mass spectrometry, we identify a Parkinson's disease enriched, cytosolic ~36-kDa α-synuclein species which can be recapitulated in Parkinson's disease model neuroblastoma cells. The characterization of subcellular-specific α-synuclein features in neurodegeneration will allow for the identification of neurotoxic α-synuclein species, which represent prime targets to reduce α-synuclein pathogenicity.
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Rashed
authors.initials: R
authors.lastname: Abdullah
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Ketan S
authors.initials: KS
authors.lastname: Patil
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rosen
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Ramavati
authors.initials: R
authors.lastname: Pal
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Shubhangi
authors.initials: S
authors.lastname: Prabhudesai
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Sungsu
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Indranil
authors.initials: I
authors.lastname: Basak
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY, 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Esthelle
authors.initials: E
authors.lastname: Hoedt
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Panick
authors.affiliation: Department of Chemistry, York College of the City University of New York, New York, NY, 11451, USA.
authors.forename: Hsin-Pin
authors.initials: HP
authors.lastname: Ho
authors.affiliation: Department of Chemistry, York College of the City University of New York, New York, NY, 11451, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chang
authors.affiliation: Center for Mitochondrial Medicine and Neurogenetics, Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Tzoulis
authors.affiliation: The Norwegian Centre for Movement Disorders, Stavanger University Hospital, 4068, Stavanger, Norway.
authors.forename: Jan Petter
authors.initials: JP
authors.lastname: Larsen
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY, 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.affiliation: The Norwegian Centre for Movement Disorders, Stavanger University Hospital, 4068, Stavanger, Norway.
authors.forename: Guido
authors.initials: G
authors.lastname: Alves
authors.affiliation: Department of Biological Sciences, St. John's University, New York, NY, 11349, USA. mollers@stjohns.edu.|The Norwegian Centre for Movement Disorders, Stavanger University Hospital, 4068, Stavanger, Norway. mollers@stjohns.edu.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Møller
mesh_terms: D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism*
keywords: Alpha-synuclein; Fractionation; Multimers; Oxidative stress; Parkinson’s disease