Dopamine differentially induces aggregation of A53T mutant and wild type α-synuclein:: Insights into the protein chemistry of Parkinson's disease

Aggregation of alpha-synuclein is known to be a causal factor in the genesis of Parkinson's disease and Dementia with Lewy bodies. Duplication and/or triplication and mutation of the alpha-synuclein gene are associated with sporadic and familial Parkinson's disease. Synucleinopathies appear to primarily affect dopaminergic neurons. The present studies investigate the role of dopamine in alpha-synuclein aggregation through NMR. Dopamine causes aggregation of both wild type and A53T mutant alpha-synuclein in a temperature-dependent manner, but the mutant A53T shows a greater propensity to aggregate in the presence of dopamine only at 37 degrees C. A single point mutation in the alpha-synuclein A53T mutant gene results in a structural change in the protein and drastically increases its propensity to aggregate in the presence of dopamine. The present data indicate that mutation in the alpha-synuclein gene may predispose the protein to dopamine-induced aggregation, thereby contributing to disease pathogenesis. (C) 2007 Elsevier Inc. All rights reserved.