Plenary Lecture
Prion-like propagation of alpha-synuclein assemblies in synucleinopathies |
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Prion-like propagation of alpha-synuclein assemblies in synucleinopathies
Ronald Melki
Paris Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91190 Gif-sur-Yvette, France
The deposition of aggregated proteins into intracellular inclusions within the central nervous system is the hallmark of several progressive neurodegenerative disorders in man. The main protein constituent of these aggregates and the affected regions within the brain differ from one neurodegenerative disorder to another. Until recently, the vicious circle consisting of spread, seeded assembly and accumulation over time within the central nervous system of misfolded proteins aggregates was thought to be restricted to the prion protein PrP. Recent reports suggest that a variety of protein aggregates spread and amplify within the central nervous system leading to distinct diseases.I will present data illustrating the propagation propensities of alpha-synuclein protein aggregates. I will discuss the nature of protein assemblies that are “Infectious”, how they bind to the cell membranes, what do they bind to and the cellular consequences of binding. I will present a quantitative assessment of their uptake, transport and export. I will show data demonstrating that alpha-synuclein pathogenic assemblies disrupt the endo-lysosomal membranes to reach the cystosol where they amplify. Finally, I will show how alpha-synuclein takes advantage of its chameleon properties to assemble into structurally and functionally distinct assemblies, we believe associated to distinct diseases. Strategies targeting the propagation of protein assemblies involved in age-related dementias will be presented and discussed.References:Pieri L et al. (2012) Fibrillar alpha-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophys J 102: 2894-905. Bousset L et al. (2013) Structural and functional characterization of two alpha-synuclein strains. Nat. Comms. 4:2575Peelaerts W et al. (2015) alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration, Nature, 522:340-4. Brahic M et al. (2016) Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1. Acta Neuropathol. 131:539-48.Shrivastava AN et al. (2015) α-synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+ gradient, EMBO J, 34:2408-23.Monsellier et al. (2016) α-Synuclein and huntingtin exon 1 amyloid fibrils bind laterally to the cellular membrane. Sci Rep. 6:219180Pieri L et al. (2016) Structural and functional properties of prefibrillar α-synuclein oligomers. Sci Rep. 6:24526Flavin W et al. (2017) Endocytic vesicle rupture is a conserved mechanism of cellularinvasion by amyloid proteins. Acta Neuropathol. Online DOI 10.1007/s00401-017-1722-x | | | |
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