α-synuclein overexpression induces apotosis in dopaminergic neurons (red).

Xu/Macmillan

Dopamine and α-synuclein are a toxic combination for neurons, say Jin Xu, Bruce Yankner (Children's Hospital, Boston, Massachusetts) and colleagues.

Aggregations of α-synuclein are a hallmark of Parkinson's disease (PD), and mutations in its gene are associated with familial forms of the disease. Yankner wanted to know why the protein is so toxic. When he overexpressed either wild-type or mutant forms of α-synuclein in cultured human dopaminergic neurons (DAN cells)—the cells affected in PD—a large number of the cells underwent apoptosis. In contrast, excess α-synuclein seemed to protect the nondopaminergic cortical neurons from apoptosis.

If endogenous synthesis of dopamine was blocked by the addition of a tyrosine hydroxylase inhibitor (THI), overexpression of α-synuclein no longer induced apoptosis. Thus, somehow, it is the combination of α-synuclein and dopamine that causes cell death, rather than overexpression of α-synuclein alone.

Yankner thinks the key to this α-synuclein–dopamine toxicity is the production of reactive oxygen species (ROS), which can damage cellular proteins. Dopamine synthesis produces ROS. But whereas a healthy cell can neutralize these ROS, neurons overexpressing α-synuclein cannot. In fact, excess α-synuclein increases the generation of ROS in DAN cells, and blocking this production with antioxidants inhibits cell death. Thus, Yankner suggests the α-synuclein potentiates ROS production by dopamine.

Large α-synuclein aggregates occur in PD neurons, but Yankner's team found that soluble α-synuclein, in the form of a 53–84-kD complex, induced apoptosis in the cultured neurons. This complex included 14–3-3, a chaperone protein that sequesters the proapoptotic proteins BAD and Forkhead and prevents their functioning.

Yankner says he still isn't sure what initially triggers the overexpression of α-synuclein in PD, but suggests that it may occur initially as a protective response to oxidative stress related to environmental agents and dopamine synthesis. He speculates that, once this happens, excess α-synuclein snatches up much of the 14–3-3 protein in the cell, forcing the release of the proapoptotic factors or preventing 14–3-3′s participation in ROS repair mechanisms. ▪

Reference:

Xu, J., et al.
2002
.
Nat. Med.
8
:
600
–606.