Abstract
Previous studies demonstrated that alpha-synuclein (alpha-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 alpha-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not alpha-syn oxidation, because mutagenesis of Met, His, and Tyr residues in alpha-syn did not abrogate this inhibition. However, truncation of alpha-syn at residue 125 restored the ability of alpha-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified alpha-syn residues 125-129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of alpha-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of alpha-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 alpha-syn fibrillization by inducing structural changes in alpha-syn that can occur through the interaction of dopaminochrome with the 125YEMPS129 motif of alpha-syn. These results suggest that the dopamine autoxidation can prevent alpha-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote alpha-syn aggregation in Parkinson's disease.
Highlights
Previous studies demonstrated that ␣-synuclein (␣syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted
There is a progressive loss of dopaminergic neurons in the substantia nigra pars compacta, which results in a significant decrease in dopamine levels in the striatum followed by motor impairments in Parkinson disease (PD) patients [1,2,3]
Lewy bodies (LBs) are found in the remaining dopaminergic neurons of the substantia nigra [4, 5], but they occur in other brainstem neurons as well as in those of the thalamus, hypothalamus, cortex, olfactory bulb, and other brain regions [4, 6, 7]
Summary
Previous studies demonstrated that ␣-synuclein (␣syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted Our results demonstrate a novel mechanism whereby dopaminochrome, an oxidized product of dopamine, inhibits ␣-syn fibrillization by interacting with a specific amino acid motif in the C terminus. Visualization of ␣-Syn Fibril and Spherical Oligomer Formation by EM and AFM—WT, mutant, and dopamine-modified ␣-syn samples were collected before and after incubation for EM, immuno-EM, and AFM analyses.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
