Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells.
Autosomal dominant Parkinson disease (PD) is caused by duplication or triplication of the alpha-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 alpha-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 microg ml(-1)). The mutated forms are more potent stimulators than wild-type (WT) alpha-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 microM respectively. We hypothesize that the neuroinflammation stimulated by release of an excess of normal alpha-synuclein or by release of its mutated forms can be involved in the pathobiology of PD.
Klegeris
Andis
A
Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. aklegeri@interchange.ubc.ca
Giasson
Benoit I
BI
Zhang
Hong
H
Maguire
John
J
Pelech
Steven
S
McGeer
Patrick L
PL
D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D020935:MAP Kinase Signaling System; D020125:Mutation, Missense; D013702:Temporal Lobe / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics* / Q000502:physiology*
D015850:Interleukin-6; D051844:alpha-Synuclein; D018799:Intercellular Adhesion Molecule-1