Extracellular interactions of alpha-synuclein with astrocytes and microglia linked to neuroinflammation and spread in multiple system atrophy

Abstract

Event Abstract Back to Event Extracellular interactions of alpha-synuclein with astrocytes and microglia linked to neuroinflammation and spread in multiple system atrophy Rowan A. Radford1, 2, Dario Valdinocci1, Bruno D. Viera1, Junna Hayashi1, Anwar Norazit3, Tracey C. Dickson4, Gilles J. Guillemin2, Roger S. Chung2 and Dean L. Pountney1* 1 Griffith University, Menzies Health Institute Queensland, Australia 2 Macquarie University, Motor Neuron Disease Research Group, Australia 3 University of Malaya, Faculty of Medicine, Malaysia 4 University of Tasmania, Menzies Research Institute Tasmania, Australia Multiple system atrophy (MSA), which is characterized by Parkinsonism and autonomic dysfunction, shows widespread neurodegeneration accompanied by neuroinflammation together with glial cytoplasmic inclusions (GCIs) composed of alpha-synuclein protein aggregates. As degenerating neurons release alpha-synuclein it may both mediate neuroinflammation and result in intracellular inclusion bodies following endocytosis. We have analysed astrocyte activation and microglial involvement in human brain tissue, animal and cellular models. We quantified astrocyte and microglial activation by morphometric and molecular marker analysis of MSA cases, and investigated the correlation to distance to nearest GCI as a proxy for extracellular alpha-synuclein. We obtained three-dimensional models of GFAP-positive astrocytes and Iba-1-positive microglia in MSA and control tissue and measured their morphometric properties and radial distance to GCIs. Astrocytes proximal to GCI-containing oligodendrocytes had significant morphometric characteristics of activation with a reciprocal linear correlation, whereas frequent activated microglia with internalized alpha-synuclein were found close to GCIs. Alpha-synuclein protein was also either added to glial cell cultures or injected into mouse brain to model the disease. In cell culture studies, alpha-synuclein addition caused activation of rat astrocytes and perinuclear alpha-synuclein inclusions formed selectively in rat oligodendrocytes. Activated astrocytes were also observed in close proximity to alpha-synuclein deposits in a unilateral rotenone-lesion mouse model and could be stimulated by neuron-glia transfer of alpha-synuclein aggregates in co-culture studies. Microglia-like differentiated THP-1 cells were found to take up alpha-synuclein and migrate away from the site of deposition. Moreover, unilateral injection of MSA tissue-derived alpha-synuclein into the mouse medial forebrain bundle resulted in widespread astrocyte and microglial activation in the alpha-synuclein-injected, but not sham-injected hemisphere. Taken together, our data suggests that the action of localized extracellular concentrations of alpha-synuclein may underlie both astrocytic and microglial activation as well as GCI pathological features and that microglia can function as vehicles to spread aggregate pathology. Keywords: alpha-Synuclein, Microglia, Multiple Sclerosis, Neuroinflammation, in vitro Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: Free Paper Session 2: Molecular Mechanisms of the Nervous System Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Radford RA, Valdinocci D, Viera BD, Hayashi J, Norazit A, Dickson TC, Guillemin GJ, Chung RS and Pountney DL (2016). Extracellular interactions of alpha-synuclein with astrocytes and microglia linked to neuroinflammation and spread in multiple system atrophy. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00103 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Dean L Pountney, Griffith University, Menzies Health Institute Queensland, Southport, Queensland, Australia, d.pountney@griffith.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rowan A Radford Dario Valdinocci Bruno D Viera Junna Hayashi Anwar Norazit Tracey C Dickson Gilles J Guillemin Roger S Chung Dean L Pountney Google Rowan A Radford Dario Valdinocci Bruno D Viera Junna Hayashi Anwar Norazit Tracey C Dickson Gilles J Guillemin Roger S Chung Dean L Pountney Google Scholar Rowan A Radford Dario Valdinocci Bruno D Viera Junna Hayashi Anwar Norazit Tracey C Dickson Gilles J Guillemin Roger S Chung Dean L Pountney PubMed Rowan A Radford Dario Valdinocci Bruno D Viera Junna Hayashi Anwar Norazit Tracey C Dickson Gilles J Guillemin Roger S Chung Dean L Pountney Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.