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Neurobiol Dis. 2014 Sep;69:76-92. doi: 10.1016/j.nbd.2014.05.020. Epub 2014 May 27.

Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread.

Author information

1
Institute of Neurology, Medical University Vienna, Austria. Electronic address: gabor.kovacs@meduniwien.ac.at.
2
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
3
Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary.
4
Institute of Neurology, Medical University Vienna, Austria.
5
Department of Clinical Neurology, Medical University Vienna, Austria.
6
AJ Roboscreen GmbH, Hohmannstrasse 7, 04129 Leipzig, Germany.
7
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.
8
Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary. Electronic address: laszlo@elte.hu.

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.

KEYWORDS:

endosome; ependyma; gap junction; internalisation; lysosome; mitochondria; nanotube; prion-like; spreading; α-synuclein

PMID:
24878508
DOI:
10.1016/j.nbd.2014.05.020
[Indexed for MEDLINE]

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