Mechanisms for the exosomal secretion and transmission of á- synuclein in the brain

• Published in: Journal of extracellular vesicles Vol. 7; p. 101
• Main Authors: Howitt, Jasn, Low, Ley-Hian, Sterzenbach, Ulrich, Tan, Seong-Seng
• Format: Journal Article
• Language: English
• Published: Abingdon John Wiley & Sons, Inc 01.01.2018
• Subjects: Brain; Cell culture; Exosomes; Lewy bodies; Movement disorders; Neurodegenerative diseases; Parkinson's disease; Propagation; Rodents; Secretion; Synuclein; Transgenic mice; Ubiquitination
• ISSN: 2001-3078

Background: Recent evidence implicates the transmission of a-synuclein within the brain as a pathway involved in the pathogenesis of Parkinson's disease. However, little is known about the initial cellular events that result in the propagation of pathology associated with Parkinson's disease. Methods: Cell culture was used to identify the mechanism involved in the exosomal release of a-synuclein. In vivo studies were conducted with; (1) wild type, (2) M83 a-synuclein over-expressing mice and (3) asynuclein knockout mice. Exosomes with or without a-synuclein were nasally delivered to mice and after four months the animals underwent behavioural testing before analysis of brain tissue. Results: We have identified a mechanistic pathway involving ubiquitination of a-synuclein that results in exosomal packaging and release from cells. In vivo, we administered exosomes via nasal delivery, a system we have previously identified to deliver functional exosomes to the brain. In both wild type and a-synuclein transgenic mouse brains we observed Lewy body-like aggregates after delivery of exosomes containing a-synuclein. Delivery of control exosomes did not result in brain aggregates, similarly, delivery of a-synuclein containing exosomes to a-synuclein knockout mice did not result in brain aggregates. Behavioural testing showed that animals given asynuclein containing exosomes had movement deficits in their hind limbs, whereas animals given control exosomes or a-synuclein exosomes to knockout mice did not display any behavioural deficits. Summary/Conclusion: Here we identified a mechanistic pathway for the packaging of a-synuclein into exosomes and show that these exosomes are able to propagate aggregated forms of the protein to the brains of rodents. These findings show how exosomes can transmit a-synuclein in the brain resulting in Lewy body-like aggregates and movement deficits that are found in Parkinson's disease.