title: Early exposure to paraquat sensitizes dopaminergic neurons to subsequent silencing of PINK1 gene expression in mice.
abstract: Environmental exposure, genetic modification, and aging are considered risky for Parkinson's disease (PD). How these risk factors cooperate to induce progressive neurodegeneration in PD remains largely unknown. Paraquat is an herbicide commonly used for weed and grass control. Exposure to paraquat is associated with the increased incidence of PD. In contrast to familial PD, most sporadic PD cases do not have genetic mutation, but may suffer from partial dysfunction of neuron-protective genes as aging. Using conditional transgenic RNAi, we showed that temporal silencing of PINK1 expression in adult mice increased striatal dopamine, the phenotype that could not be induced by constitutive gene silencing. Moreover, early exposure to paraquat sensitized dopaminergic neurons to subsequent silencing of PINK1 gene expression, leading to a significant loss of dopaminergic neurons. Our findings suggest a novel pathogenesis of PD: exposure to environmental toxicants early in the life reduces the threshold of developing PD and partial dysfunction of neuron-protective genes later in the life initiates a process of progressive neurodegeneration to cross the reduced threshold of disease onset.
authors: Department of Neurology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Hongxia.zhou@jefferson.edu
authors: Hongxia
authors: H
authors: Zhou
authors: Cao
authors: C
authors: Huang
authors: Jianbin
authors: J
authors: Tong
authors: Xu-Gang
authors: XG
authors: Xia
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004781:Environmental Exposure; D020868:Gene Silencing / Q000187:drug effects*; D006652:Histological Techniques; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology*; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000378:metabolism*; D034622:RNA Interference; D000099202:PTEN-Induced Putative Kinase
chemical_list: D017931:DNA Primers; D004298:Dopamine; D010269:Paraquat; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase