title: Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread.
abstract: Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated α-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-α-synuclein 5G4 antibody; 2) evaluated immunoreactivity patterns and their correlation in human brain tissue with micro- and astrogliosis in 57 cases with PD or DLB; and 3) performed a systematic immunoelectron microscopical mapping of subcellular localizations. 5G4 strongly binds to the high molecular weight fraction of β-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated α-synuclein including perivascular macrophages, ependyma and cranial nerves. α-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic α-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated α-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated α-synuclein plays a key role in the molecular-structural cytopathogenesis of disorders with Lewy bodies. We conclude that 1) the 5G4 antibody has strong selectivity for β-sheet rich α-synuclein oligomers; 2) Lewy bodies themselves are not the most relevant morphological substrate that evokes tissue lesioning; 3) both neurons and astrocytes internalize disease-associated α-synuclein in the human brain, suggesting prion-like cell-to-cell spread of α-synuclein by uptake from surrounding structures, as shown previously in experimental observations.
authors.affiliation: Institute of Neurology, Medical University Vienna, Austria. Electronic address: gabor.kovacs@meduniwien.ac.at.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Breydo
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Green
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary.
authors.forename: Viktor
authors.initials: V
authors.lastname: Kis
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary.
authors.forename: Gina
authors.initials: G
authors.lastname: Puska
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Lőrincz
authors.affiliation: Institute of Neurology, Medical University Vienna, Austria.
authors.forename: Laura
authors.initials: L
authors.lastname: Perju-Dumbrava
authors.affiliation: Institute of Neurology, Medical University Vienna, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Giera
authors.affiliation: Department of Clinical Neurology, Medical University Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Pirker
authors.affiliation: Institute of Neurology, Medical University Vienna, Austria.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Lutz
authors.affiliation: AJ Roboscreen GmbH, Hohmannstrasse 7, 04129 Leipzig, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Lachmann
authors.affiliation: Institute of Neurology, Medical University Vienna, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary.
authors.forename: Kinga
authors.initials: K
authors.lastname: Molnár
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary. Electronic address: laszlo@elte.hu.
authors.forename: Lajos
authors.initials: L
authors.lastname: László
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005911:Gliosis / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D016631:Lewy Bodies / Q000378:metabolism; D020961:Lewy Body Disease / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: endosome; ependyma; gap junction; internalisation; lysosome; mitochondria; nanotube; prion-like; spreading; α-synuclein