Washington: Researchers have found that genetic mutation combined with exposure to pesticides increases risk of Parkinson's disease and other neurodegenerative diseases, by killing dopamine-containing neurons.
Senior author of the study, Stuart Lipton from Sanford-Burnham Medical Research Institute said that his team used human stem cells derived from Parkinson's disease patients to show that genetic mutation and pesticides create a 'double hit' scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death.
In the study, Lipton, along with Rajesh Ambasudhan, assistant professor and Rudolf Jaenisch, professor at the Massachusetts Institute of Technology, used skin cells from Parkinson's patients that had a mutation in the gene encoding a protein called alpha-synuclein.
Alpha-synuclein is the primary protein found in Lewy bodies, protein clumps that are the pathological hallmark of Parkinson's disease.
Using patient skin cells, the researchers created human induced pluripotent stem cells (hiPSCs) containing the mutation, and then "corrected" the alpha-synuclein mutation in other cells.
Next, they reprogrammed all of these cells to become the specific type of nerve cell that is damaged in Parkinson's disease, called A9 dopamine-containing neurons, thus creating two sets of neurons, identical in every respect except for the alpha-synuclein mutation.
Frank Soldner, research scientist in Jaenisch's lab and co-author of the study, said that exposing both normal and mutant neurons to pesticides, including paraquat, maneb and rotenone, created excessive free radicals in cells with the mutation, causing damage to dopamine-containing neurons that led to cell death.
In this case, the researchers were able to pinpoint how cells with the mutation, when exposed to pesticides, disrupt a key mitochondrial pathway, called MEF2C-PGC1alpha, which normally protects neurons that contain dopamine.
The study is published online in Cell.