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

Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated alpha-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-alpha-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 beta-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated alpha-synuclein including perivascular macrophages, ependyma and cranial nerves. alpha-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic alpha-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated alpha-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated alpha-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 beta-sheet rich alpha-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 alpha-synuclein in the human brain, suggesting prion-like cell-to-cell spread of alpha-synuclein by uptake from surrounding structures, as shown previously in experimental observations. (C) 2014 Elsevier Inc. All rights reserved.