The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions.
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, 90μm(2)) between mean process length and radial distance to the nearest GCI (R(2), 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.
Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
Rowan
R
Radford
Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
Alex
A
Rcom-H'cheo-Gauthier
Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
Mathew B
MB
Wong
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Emma D
ED
Eaton
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Marion
M
Quilty
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Catherine
C
Blizzard
Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Anwar
A
Norazit
Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
Adrian
A
Meedeniya
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
James C
JC
Vickers
School of Human Physiology, Flinders University of South Australia, Adelaide, Australia.
Wei Ping
WP
Gai
School of Advanced Medicine, Macquarie University, Sydney, Australia.
Gilles J
GJ
Guillemin
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Adrian K
AK
West
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Tracey C
TC
Dickson
School of Advanced Medicine, Macquarie University, Sydney, Australia.
Roger
R
Chung
Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia. Electronic address: d.pountney@griffith.edu.au.
Dean L
DL
Pountney
D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019578:Multiple System Atrophy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051844:alpha-Synuclein / Q000378:metabolism* / Q000494:pharmacology
D051844:alpha-Synuclein
Alpha-synuclein; Multiple system atrophy; Neuroinflammation; Progressive supranuclear palsy; Quantitative morphometry