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, L. László

Research output: Contribution to journalArticle

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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 - 2014

Fingerprint

Synucleins
Prions
Brain
Lewy Bodies
Parkinson Disease
Ependyma
Multiple System Atrophy
Neurons
Lewy Body Disease
Neuropil
Cranial Nerves
Antibodies
Neuroglia
Astrocytes
Dementia
Mitochondria

Keywords

  • Endosome
  • Ependyma
  • Gap junction
  • Internalisation
  • Lysosome
  • Mitochondria
  • Nanotube
  • Prion-like
  • Spreading
  • α-synuclein

ASJC Scopus subject areas

  • Neurology
  • Medicine(all)

Cite this

Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread. / Kovacs, Gabor G.; Breydo, Leonid; Green, Ryan; Kis, Viktor; Puska, Gina; Lorincz, Péter; Perju-Dumbrava, Laura; Giera, Regina; Pirker, Walter; Lutz, Mirjam; Lachmann, Ingolf; Budka, Herbert; Uversky, Vladimir N.; Molnár, Kinga; László, L.

In: Neurobiology of Disease, Vol. 69, 2014, p. 76-92.

Research output: Contribution to journalArticle

Kovacs, GG, Breydo, L, Green, R, Kis, V, Puska, G, Lorincz, P, Perju-Dumbrava, L, Giera, R, Pirker, W, Lutz, M, Lachmann, I, Budka, H, Uversky, VN, 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, vol. 69, pp. 76-92. https://doi.org/10.1016/j.nbd.2014.05.020
Kovacs, Gabor G. ; Breydo, Leonid ; Green, Ryan ; Kis, Viktor ; Puska, Gina ; Lorincz, Péter ; Perju-Dumbrava, Laura ; Giera, Regina ; Pirker, Walter ; Lutz, Mirjam ; Lachmann, Ingolf ; Budka, Herbert ; Uversky, Vladimir N. ; Molnár, Kinga ; László, L. / Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread. In: Neurobiology of Disease. 2014 ; Vol. 69. pp. 76-92.
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