Cytokines disrupt intracellular patterns of Parkinson's disease-associated proteins alpha-synuclein, tau and ubiquitin in cultured glial cells.
The purpose of this study was to determine the effects of specific proinflammatory cytokines interleukin-6 (Il-6), interleukin-1beta (Il-1beta), interferon-gamma (IFN), and tumor necrosis factor-alpha (TNFalpha), on content and distribution of alpha-synuclein (alpha-synuclein), tau and ubiquitin in human derived cultured glial cells. Exposure paradigms mimicked acute (2 h), intermediate (18 h) and prolonged time frames (96 h); consisting of single or repeated low doses (10 ng/ml) or high doses (50 ng/ml), consistent with either mild or serious systemic infectious/inflammatory responses. Images of intracellular protein content and distribution were reconstructed from emission patterns generated by fluorescence deconvolution microscopy. Minor alterations were seen in protein content with IFN; Il-1beta decreased alpha-synuclein and tau at 18 and 96 h; TNFalpha inversely reduced alpha-synuclein and increased ubiquitin content. Combinations of Il-1beta and IFN produced a robust increase of alpha-synuclein and tau at 2 h. Consecutive low doses of Il-6 produced only minor increases in alpha-synuclein and ubiquitin after 4 h, whereas a single high dose resulted in major increases for all three proteins over the first 18 h. Protein localization patterns were distinctly different and were altered dependent upon cytokine treatment. A high dose exposure (2 x 50 ng/ml) with Il-6 and IFN demonstrated that protein increases and dispersals could be sustained and that the normal perinuclear tau and peripheral alpha-synuclein patterns were disrupted. These results support the postulate that specific cytokines affect temporal protein changes with concomitant pattern disruptions, possibly reflecting a mechanism of cell dysfunction in Parkinson's degeneration.
Bick
Roger J
RJ
Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Texas 77030, USA. Roger.J.Bick@uth.tmc.edu
Poindexter
Brian J
BJ
Kott
Marylee M
MM
Liang
Yang An
YA
Dinh
Kha
K
Kaur
Berneet
B
Bick
Diane L M
DL
Doursout
Marie-Francoise
MF
Schiess
Mya C
MC
D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D009457:Neuroglia / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016207:Cytokines; D025801:Ubiquitin; D051844:alpha-Synuclein; D016875:tau Proteins