Dopamine differentially induces aggregation of A53T mutant and wild type alpha-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.
Department of Biochemistry, Molecular and Cell Biology, and Georgetown University, Washington, DC 20007, USA.
Charbel E-H
CE
Moussa
Fatemeh
F
Mahmoodian
York
Y
Tomita
Anita
A
Sidhu
D002460:Cell Line; D004298:Dopamine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D051844:alpha-Synuclein; D004298:Dopamine