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Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells

Andis Klegeris^*,1, Benoit I. Giasson^¶, Hong Zhang, John Maguire, Steven Pelech^, and Patrick L. McGeer^*

^* Kinsmen Laboratory of Neurological Research,

Department of Pathology and Laboratory Medicine and

Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada;

^¶ Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA; and

Kinexus Bioinformatics Corporation, Vancouver, British Columbia, Canada

¹Correspondence: Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. E-mail: aklegeri{at}interchange.ubc.ca

Autosomal dominant Parkinson disease (PD) is caused by duplication or triplication of the -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 -synuclein strongly stimulates human astrocytes as well as human U-373 MG astrocytoma cells to up-regulate both interleukin (IL)-6 and ICAM-1 (ED₅₀=5 µg ml^–1). The mutated forms are more potent stimulators than wild-type (WT) -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 IC₅₀ values of 2, 5, and 1.5 µM respectively. We hypothesize that the neuroinflammation stimulated by release of an excess of normal -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. Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells.

Key Words: c-Jun N-terminal kinase • MAPK/ERK kinase • neuroinflammation • p38 mitogen-activated protein kinase • Parkinson disease