title: Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis-related genes in mice models of Parkinson's disease.
abstract: BACKGROUND
  Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb (MB) in rural workers increases the risk for PD and exposure of adult mice to MB/PQ results in dopamine fiber loss and decreased locomotor activity. While PD is characterized by neuronal loss in the substantia nigra, we previously showed that accumulation of α-synuclein in the limbic system contributes to neurodegeneration by interfering with adult neurogenesis.
  
  
  RESULTS
  We investigated the effect of pesticides on adult hippocampal neurogenesis in two transgenic models: Line 61, expressing the human wild type SNCA gene and Line LRRK2(G2019S), expressing the human LRRK2 gene with the mutation G2019S. Combined exposure to MB/PQ resulted in significant reduction of neuronal precursors and proliferating cells in non-transgenic animals, and this effect was increased in transgenic mice, in particular for Line 61, suggesting that α-synuclein accumulation and environmental toxins have a synergistic effect. We further investigated the transcription of 84 genes with direct function on neurogenesis. Overexpresion of α-synuclein resulted in the downregulation of 12% of target genes, most of which were functionally related to cell differentiation, while LRRK2 mutation had a minor impact on gene expression. MB/PQ also affected transcription in non-transgenic backgrounds, but when transgenic mice were exposed to the pesticides, profound alterations in gene expression affecting 27% of the studied targets were observed in both transgenic lines. Gene enrichment analysis showed that 1:3 of those genes were under the regulation of FoxF2 and FoxO3A, suggesting a primary role of these proteins in the response to genetic and environmental cues.
  
  
  CONCLUSIONS
  We report that adult neurogenesis is highly susceptible to multiple "risk factors" for PD, including α-synuclein accumulation, LRRK2 G2019 mutation and exposure to environmental toxins. We identified specific groups of genes that are responsive to each stressor, while uncovering a novel function for Fox transcription factors in PD.
authors.affiliation: Department of Neuroscience, University of California San Diego, 9500 Gilman Dr,, MTF 344, La Jolla, CA 92093-0624, USA. pdesplat@ucsd.edu
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.forename: Pruthul
authors.initials: P
authors.lastname: Patel
authors.forename: Kori
authors.initials: K
authors.lastname: Kosberg
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Masayo
authors.initials: M
authors.lastname: Fujita
authors.forename: Makoto
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D059647:Gene-Environment Interaction; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects*; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000235:genetics; D010575:Pesticides / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D010575:Pesticides; C497604:SNCA protein, human; D051844:alpha-Synuclein; D008344:Maneb; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D010269:Paraquat