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

Gabor G. Kovacs, Leonid Breydo, Ryan Green, Viktor Kis, Gina Puska, Péter Lorincz, Laura Perju-Dumbrava, Regina Giera, Walter Pirker, Mirjam Lutz, Ingolf Lachmann, Herbert Budka, Vladimir N. Uversky, Kinga Molnár, Lajos László

Research output: Article

71 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)76-92
Number of pages17
JournalNeurobiology of Disease
Volume69
DOIs
Publication statusPublished - szept. 2014

ASJC Scopus subject areas

  • Neurology

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    Kovacs, G. G., Breydo, L., Green, R., Kis, V., Puska, G., Lorincz, P., Perju-Dumbrava, L., Giera, R., Pirker, W., Lutz, M., Lachmann, I., Budka, H., Uversky, V. N., Molnár, K., & László, L. (2014). Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiology of Disease, 69, 76-92. https://doi.org/10.1016/j.nbd.2014.05.020