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The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions

Citation

Radford, R and Rcom-H'cheo-Gauthier, A and Wong, MB and Eaton, ED and Quilty, M and Blizzard, C and Norazit, A and Meedeniya, A and Vickers, JC and Gai, WP and Guillemin, GJ and West, AK and Dickson, TC and Chung, R and Pountney, DL, The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions, Molecular and Cellular Neuroscience, 65 pp. 68-81. ISSN 1044-7431 (2015) [Refereed Article]

Copyright Statement

Copyright 2015 Elsevier

DOI: doi:10.1016/j.mcn.2015.02.015

Abstract

Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained "skinned" three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n = 75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to the GCI. Astrocytes proximal to GCI-containing oligodendrocytes (r < 25μm) had significantly (p, 0.05) longer and thicker processes characteristic of activation than distal astrocytes (r > 25μm), with a reciprocal linear correlation (m, 90μm2) between mean process length and radial distance to the nearest GCI (R2, 0.7). In primary cell culture studies, α-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear α-syn inclusions in mature (MOSP-positive) rat oligodendrocytes. Activated astrocytes were also observed in close proximity to α-syn deposits in a unilateral rotenone-lesion mouse model. Moreover, unilateral injection of MSA tissue-derived α-syn into the mouse medial forebrain bundle resulted in widespread neuroinflammation in the α-syn-injected, but not sham-injected hemisphere. Taken together, our data suggests that the action of localized concentrations of α-syn may underlie both astrocyte and oligodendrocyte MSA pathological features.

Item Details

Item Type:Refereed Article
Keywords:alpha-synuclein, multiple system atrophy, neuroinflammation, progressive supranuclear palsy, quantitative morphometry
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurology and Neuromuscular Diseases
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Eaton, ED (Dr Emma Eaton)
Author:Quilty, M (Miss Marian Quilty)
Author:Blizzard, C (Dr Catherine Blizzard)
Author:Vickers, JC (Professor James Vickers)
Author:West, AK (Professor Adrian West)
Author:Dickson, TC (Associate Professor Tracey Dickson)
ID Code:99270
Year Published:2015
Web of Science® Times Cited:10
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-03-18
Last Modified:2017-11-06
Downloads:0

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