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Alpha‐synuclein and its disease‐causing mutants induce ICAM‐1 and IL‐6 in human astrocytes and astrocytoma cells
Author(s) -
Klegeris Andis,
Giasson Benoit I.,
Zhang Hong,
Maguire John,
Pelech Steven,
McGeer Patrick L.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6183com
Subject(s) - neuroinflammation , kinase , mapk/erk pathway , alpha synuclein , astrocyte , protein kinase a , microbiology and biotechnology , biology , p38 mitogen activated protein kinases , microglia , chemistry , inflammation , immunology , endocrinology , central nervous system , medicine , parkinson's disease , disease
Autosomal dominant Parkinson disease (PD) is caused by duplication or triplication of the α‐synuclein gene as well as by the A30P, E46K, and A53T mutations. The mechanisms are unknown. Reactive astrocytes in the substantia nigra of PD and MPTP‐treated monkeys display high levels of the inflammatory mediator intercellular adhesion molecule‐1 (ICAM‐1), indicating that chronic inflammation contributes to the degeneration. Here we report that α‐synuclein strongly stimulates human astrocytes as well as human U‐373 MG astrocytoma cells to up‐regulate both interleukin (IL)‐6 and ICAM‐1 (ED 50 5 µg ml –1 ). The mutated forms are more potent stimulators than wild‐type (WT) α‐synuclein in these assays. We demonstrate by immunoblotting analysis that this up‐regulation is associated with activation of the major mitogen‐activated protein kinase (MAPK) pathways. It is also attenuated by PD 98059, an inhibitor of the MAPK/extracellular‐regulated kinase kinase MEK1/2, SP 600125, an inhibitor of c‐Jun N‐terminal kinase (JNK), and SB 202190, an inhibitor of p38 MAPK. The inhibitory effects on human astrocytes have IC 50 values of 2, 5, and 1.5 M respectively. We hypothesize that the neuroinflammation stimulated by release of an excess of normal α‐synuclein or by release of its mutated forms can be involved in the pathobiology of PD.—Klegeris, A., Giasson, B. I., Zhang, H., Maguire, J., Pelech, S., McGeer, P. L. Alphaα‐synuclein and its disease‐causing mutants induce ICAM‐1 and IL‐6 in human astrocytes and astrocytoma cells. FASEB J. 20, 2000–2008 (2006)