Alpha-synuclein expression modulates microglial activation phenotype.
Recent Parkinson's disease research has focused on understanding the function of the cytosolic protein, alpha-synuclein, and its contribution to disease mechanisms. Within neurons, alpha-synuclein is hypothesized to have a role in regulating synaptic plasticity, vesicle release, and trafficking. In contrast, glial-expressed alpha-synuclein remains poorly described. Here, we examine the consequence of a loss of alpha-synuclein expression on microglial activation. Using a postnatal brain-derived culture system, we defined the phenotype of microglia from wild-type and knock-out alpha-synuclein mice (Scna-/-). Scna-/- microglia displayed a basally increased reactive phenotype compared with the wild-type cells and an exacerbated reactive phenotype after stimulation. They also exhibited dramatic morphologic differences compared with wild-type, presenting as large, ramified cells filled with vacuole-like structures. This corresponded with increased protein levels of activation markers, CD68 and beta1 integrin, in the Scna-/- cells. More importantly, Scna-/- microglia, after stimulation, secreted elevated levels of proinflammatory cytokines, TNFalpha (tumor necrosis factor alpha) and IL-6 (interleukin-6), compared with wild type. However, despite the reactive phenotype, Scna-/- cells had impaired phagocytic ability. We demonstrate for the first time that alpha-synuclein plays a critical role in modulating microglial activation state. We suggest that altered microglial alpha-synuclein expression will affect their phenotype as has already been demonstrated in neurons. This has direct ramifications for the contribution of microglia to the pathophysiology of disease, particularly in familial cases linked to altered alpha-synuclein expression.
Austin
Susan A
SA
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota 58202-9037, USA.
Floden
Angela M
AM
Murphy
Eric J
EJ
Combs
Colin K
CK
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D051844:alpha-Synuclein