Both the protein α-synuclein, one of the major components of Lewy bodies, and the neurotransmitter dopamine have come under scrutiny as potential mediators of the neuronal loss in the substantia nigra that occurs in Parkinson's disease. These two molecules are now linked by new evidence, reported in today's Science, which indicates that dopamine-derived orthoquinone (DAQ) can form an adduct with α-synuclein that inhibits its fibrillization.
Peter Lansbury, of Brigham and Women's Hospital, Boston, and colleagues, tested compound libraries for molecules that would interfere with the dynamics of synuclein protofibril polymerization into longer fibrils and could therefore prove useful in probing the relation between the protein and disease progression. An initial screen of 169 compounds turned up 15 fibril inhibitors, including dopamine and 13 structurally related catecholamines. Subsequent experiments showed that dopamine not only inhibited fibril formation but also formed a covalent adduct with α-synuclein. Antioxidants prevented both adduct formation and fibril inhibition, suggesting that these effects may be mediated by an oxidized derivative of dopamine such as DAQ, which is known to react with cysteine and tyrosine residues.
The researchers isolated the protein adduct and showed that it could inhibit fibril formation. It also increased the half-life of protofibrils, which Lansbury and others predict to be the pathogenic form of the protein. "This was an intriguing finding," said Lansbury, who was planning on screening thousands of unknown molecules, "that dopamine was responsible for something that we had thought would promote the disease." This finding may help explain why dopaminergic neurons are especially vulnerable in Parkinson's.
The group is now focused on perfecting a technique that will allow detection of α-synuclein adducts in brain extracts.—Tom Fagan
No Available References
No Available Further Reading
- Conway KA, Rochet JC, Bieganski RM, Lansbury PT. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science. 2001 Nov 9;294(5545):1346-9. PubMed.