title: Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes.
abstract: Parkinson's disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.
authors.affiliation: Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Domert
authors.affiliation: Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sackmann
authors.affiliation: Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Severinsson
authors.affiliation: Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Agholme
authors.affiliation: Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University,Uppsala,Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Bergström
authors.affiliation: Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University,Uppsala,Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.affiliation: Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0001-6716-0314
authors.initials: M
authors.lastname: Hallbeck
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D066329:Protein Aggregates; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein