Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis-related genes in mice models of Parkinson’s disease

Molecular Neurodegeneration

Eliezer Masliah³  Makoto Hashimoto²  Masayo Fujita²  Edward Rockenstein¹  Christina Patrick¹  Michael Mante¹  Kori Kosberg¹  Pruthul Patel¹  Paula Desplats¹ 

[1] Department of Neuroscience, University of California San Diego, 9500 Gilman Dr., MTF 344, La Jolla, CA, 92093-0624, USA;Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Tokyo, 183-8526, Japan;Department of Pathology, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0624, USA

关键词: Gene x environment interactions;    Gene expression;    Environmental exposure;    Pesticides;    Paraquat;    Maneb;    Parkinson’s disease;    Adult neurogenesis;   

Others  :  863768
DOI  :  10.1186/1750-1326-7-49

 received in 2012-05-21, accepted in 2012-09-24,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Desplats et al.; licensee BioMed Central Ltd.

【 图 表 】

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