Pesticides directly accelerate the rate of alpha-synuclein fibril formation: a possible factor in Parkinson's disease.
Parkinson's disease involves intracellular deposits of alpha-synuclein in the form of Lewy bodies and Lewy neurites. The etiology of the disease is unknown, however, several epidemiological studies have implicated environmental factors, especially pesticides. Here we show that several pesticides, including rotenone, dieldrin and paraquat, induce a conformational change in alpha-synuclein and significantly accelerate the rate of formation of alpha-synuclein fibrils in vitro. We propose that the relatively hydrophobic pesticides preferentially bind to a partially folded intermediate conformation of alpha-synuclein, accounting for the observed conformational changes, and leading to association and subsequent fibrillation. These observations suggest one possible underlying molecular basis for Parkinson's disease.
Uversky
V N
VN
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
Li
J
J
Fink
A L
AL
D002942:Circular Dichroism; D004026:Dieldrin / Q000737:chemistry / Q000494:pharmacology; D004050:Ditiocarb / Q000737:chemistry / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D010269:Paraquat / Q000737:chemistry / Q000494:pharmacology; D010300:Parkinson Disease / Q000209:etiology*; D010575:Pesticides / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D012402:Rotenone / Q000737:chemistry / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D010575:Pesticides; D051843:Synucleins; D051844:alpha-Synuclein; D012402:Rotenone; D004050:Ditiocarb; D004026:Dieldrin; D010269:Paraquat