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.