Details

Autor(en) / Beteiligte

• Norris, Erin H.
• Giasson, Benoit I.
• Hodara, Roberto
• Xu, Shaohua
• Trojanowski, John Q.
• Ischiropoulos, Harry
• Lee, Virginia M.-Y.

Titel

Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations

Ist Teil von

• The Journal of biological chemistry, 2005-06, Vol.280 (22), p.21212-21219

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• Previous studies demonstrated that α-synuclein (α-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. (2001) Science 294, 1346–1349). Dopamine inhibition of α-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not α-syn oxidation, because mutagenesis of Met, His, and Tyr residues in α-syn did not abrogate this inhibition. However, truncation of α-syn at residue 125 restored the ability of α-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified α-syn residues 125–129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of α-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of α-syn fibrillization. Dopaminochrome promotes the formation of spherical oligomers by inducing conformational changes, as these oligomers regained the ability to fibrillize by simple denaturation/renaturation. Taken together, these data indicate that dopamine inhibits α-syn fibrillization by inducing structural changes in α-syn that can occur through the interaction of dopaminochrome with the 125YEMPS129 motif of α-syn. These results suggest that the dopamine autoxidation can prevent α-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote α-syn aggregation in Parkinson's disease.