Journal Article

Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes

Agholme, Lotta, Domert, Jakob, Severinsson, Emelie, Ingelsson, Martin, Hallbeck, Martin, Bergström, Joakim, Sackmann, Christopher

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aggregates / alpha-Synuclein - chemistry / alpha-Synuclein - metabolism / alpha-Synuclein - toxicity / Alzheimer's disease / Alzheimers disease / amyloid-beta peptide / Anatomy / Autophagy / Biology and Life Sciences / Brain / Brain architecture / Brain research / Cell culture / Cell Differentiation - drug effects / Cell Line, Tumor / cerebrospinal-fluid / Coculture Techniques / Confocal microscopy / Dementia / Endosomes - drug effects / Endosomes - metabolism / Fibrils / Geriatrics / Humans / in-vivo / Introduced species / Laboratories / Localization / Lysosomes / Lysosomes - drug effects / Lysosomes - metabolism / Medicine / Medicine and Health Sciences / Microscopy / mitochondria / Monomers / Neural circuitry / Neurodegeneration / Neurodegenerative diseases / Neurological diseases / Neurons / Neurons - cytology / Neurosciences / Neurovetenskaper / Oligomers / Parkinson's disease / Parkinsons disease / Pathology / pathway / Physical Sciences / Physiological aspects / Protein Aggregates / Protein Multimerization / Protein Structure, Quaternary / Protein Transport / Public health / Research and Analysis Methods / Science & Technology - Other Topics / Seeding / Species / Spreading / Studies / Synapses - drug effects / Synapses - metabolism / Synuclein / Three dimensional models / transmission