Project Title
Uncovering the role of non-coding genetic variation in gene-pesticide interaction in Parkinson´s disease
Partner Organisations
University of Chile
Internal ID
1251006
Principal Investigator
PATRICIO ALEJANDRO OLGUIN AGUILERA
Type
basic research
Status
VIGENTE
Start Date
April 1, 2025
End Date
April 1, 2029
Investigators
Description
Parkinson's disease (PD) is the most prevalent neurodegenerative movement disorder, affecting over 10
million worldwide. However, neither environmental factors nor genetic variation explains the high prevalence
of PD, suggesting that gene-environment interaction plays a key role. Since 90% of PD risk variants localize
in non-coding and regulatory regions, most of the gene-environment interaction effects could be explained
by non-coding variation. Pesticide exposure affecting the mitochondrial complex-1, such as rotenone and
lambda-cyhalothrin, is a well-described PD environmental risk factor. We recently conducted a genome-wide
association study to identify genetic variation associated with the differential phenotypic response to the
pesticide rotenone in Drosophila, a well-characterized model of idiopathic PD. We found that genetic variants
in the non-coding regions of genes associated with the innate immune response mediated by Toll and in two
of its potential targets are associated with differential effects of rotenone exposure in locomotion and sleep,
two hallmark behaviors altered in PD. These genes have been linked functionally with PD, and the expression
of dMLF and ergic53 are affected in iPSCs-derived dopaminergic neurons from PD patients with disrupted
mitochondrial function. Moreover, multiple non-coding variants associated with gene-pesticide exposure
interaction localize in the Dorsal/NF-κB binding site in dMlF and dMCFD2. The Dorsal/NF-κB transcription
factor is a Toll effector linked to neuroinflammation and PD. Thus, we hypothesize that non-coding
genetic variation modifies the effects of rotenone exposure in behavioral and cellular Parkinsonlike phenotypes by affecting gene expression in specific neural cells involved in the response to
rotenone exposure. We propose that non-coding variation interacts with rotenone exposure at
two levels in neurons and glial cells: modifying the transcriptional response to rotenone exposure
or the basal expression of genes involved in the cellular and molecular responses to rotenone.
Therefore, modification of gene expression in specific cell types modifies the effects of rotenone
in behavioral and cellular Parkinson's-like phenotypes.
At the mechanistic level, we hypothesize that non-coding genetic variation modifies the innate
immune response mediated by Toll signaling, altering the transcriptional response of dMlf,
ergic53, Drs, and dMCFD2 to rotenone. Specifically, in the case of dMlf and dMCFD2 affecting the
interaction of the Dorsal/NF-κB transcription factor to its binding site after activation of Toll
receptor by rotenone exposure in dopaminergic neurons.
We propose the following aims:
To determine the role of non-coding genetic variation in the effects of rotenone exposure in
hallmark PD-like phenotypes in Drosophila. Here, we will answer whether genetic variation associated
with candidate genes Drs, dMlf, MCFD2, and ergic53 underlies variable phenotypic responses to rotenone
regarding severity and progression. We will analyze sleep and climbing behavior, dopaminergic neuron
degeneration, and dopamine content in the Drosophila brain throughout adulthood. We expect genetic
variation to modify pesticide effects in the severity and progression of PD-like hallmark phenotypes.
To determine the role of non-coding genetic variation in the transcriptional response to rotenone exposure. First, we will identify candidate loci that respond transcriptionally to rotenone in the brain and
specific cellular populations. By determining the concordance between differentially expressed genes and
non-coding variants, we will identify candidate cis-expression quantitative loci (eQTLs). Then, using fixed
allele populations and CRISPR-generated alleles, we will functionally validate a group of candidates and
determine whether genetic variants modify the transcriptional responses to rotenone or basal gene
expression levels in the brain and specific cell types. We expect that rotenone affects the expression of
candidate genes involved in the innate immune response and other genes in different cell types.
To determine the role of gene expression in different cell types in PD-like phenotypes caused by
rotenone exposure and the role of the Toll signaling pathway. Since signaling pathways, including Toll
signaling, can act in both neurons and glial cells, promoting neurodegeneration, we will use the genetic tools
of Drosophila to control gene expression in a cell and time-specific manner to map the neural cell type(s)
where the expression levels of Drs, dMlf, MCFD2, and ergic53 interacts with rotenone exposure contributing
to variation in PD-like phenotypes severity and progression. Finally, we will determine whether the Dorsal/NFκB protein interacts with the transcription factor binding site located upstream of dMlf and in the third intron
of dMCFD2 and whether gene-pesticide exposure interaction candidate alleles and rotenone exposure affect
this interaction.
Uncovering the molecular mechanisms by which non-coding variants modify the effects of pesticides, leading
to increased PD risk, severity, and progression, and the cellular context where these mechanisms operate
will contribute to understanding PD at the organism level and the design of personalized new therapeutic
strategies aimed at reducing the risk and severity and progression of the disease in individuals exposed to
pesticides
million worldwide. However, neither environmental factors nor genetic variation explains the high prevalence
of PD, suggesting that gene-environment interaction plays a key role. Since 90% of PD risk variants localize
in non-coding and regulatory regions, most of the gene-environment interaction effects could be explained
by non-coding variation. Pesticide exposure affecting the mitochondrial complex-1, such as rotenone and
lambda-cyhalothrin, is a well-described PD environmental risk factor. We recently conducted a genome-wide
association study to identify genetic variation associated with the differential phenotypic response to the
pesticide rotenone in Drosophila, a well-characterized model of idiopathic PD. We found that genetic variants
in the non-coding regions of genes associated with the innate immune response mediated by Toll and in two
of its potential targets are associated with differential effects of rotenone exposure in locomotion and sleep,
two hallmark behaviors altered in PD. These genes have been linked functionally with PD, and the expression
of dMLF and ergic53 are affected in iPSCs-derived dopaminergic neurons from PD patients with disrupted
mitochondrial function. Moreover, multiple non-coding variants associated with gene-pesticide exposure
interaction localize in the Dorsal/NF-κB binding site in dMlF and dMCFD2. The Dorsal/NF-κB transcription
factor is a Toll effector linked to neuroinflammation and PD. Thus, we hypothesize that non-coding
genetic variation modifies the effects of rotenone exposure in behavioral and cellular Parkinsonlike phenotypes by affecting gene expression in specific neural cells involved in the response to
rotenone exposure. We propose that non-coding variation interacts with rotenone exposure at
two levels in neurons and glial cells: modifying the transcriptional response to rotenone exposure
or the basal expression of genes involved in the cellular and molecular responses to rotenone.
Therefore, modification of gene expression in specific cell types modifies the effects of rotenone
in behavioral and cellular Parkinson's-like phenotypes.
At the mechanistic level, we hypothesize that non-coding genetic variation modifies the innate
immune response mediated by Toll signaling, altering the transcriptional response of dMlf,
ergic53, Drs, and dMCFD2 to rotenone. Specifically, in the case of dMlf and dMCFD2 affecting the
interaction of the Dorsal/NF-κB transcription factor to its binding site after activation of Toll
receptor by rotenone exposure in dopaminergic neurons.
We propose the following aims:
To determine the role of non-coding genetic variation in the effects of rotenone exposure in
hallmark PD-like phenotypes in Drosophila. Here, we will answer whether genetic variation associated
with candidate genes Drs, dMlf, MCFD2, and ergic53 underlies variable phenotypic responses to rotenone
regarding severity and progression. We will analyze sleep and climbing behavior, dopaminergic neuron
degeneration, and dopamine content in the Drosophila brain throughout adulthood. We expect genetic
variation to modify pesticide effects in the severity and progression of PD-like hallmark phenotypes.
To determine the role of non-coding genetic variation in the transcriptional response to rotenone exposure. First, we will identify candidate loci that respond transcriptionally to rotenone in the brain and
specific cellular populations. By determining the concordance between differentially expressed genes and
non-coding variants, we will identify candidate cis-expression quantitative loci (eQTLs). Then, using fixed
allele populations and CRISPR-generated alleles, we will functionally validate a group of candidates and
determine whether genetic variants modify the transcriptional responses to rotenone or basal gene
expression levels in the brain and specific cell types. We expect that rotenone affects the expression of
candidate genes involved in the innate immune response and other genes in different cell types.
To determine the role of gene expression in different cell types in PD-like phenotypes caused by
rotenone exposure and the role of the Toll signaling pathway. Since signaling pathways, including Toll
signaling, can act in both neurons and glial cells, promoting neurodegeneration, we will use the genetic tools
of Drosophila to control gene expression in a cell and time-specific manner to map the neural cell type(s)
where the expression levels of Drs, dMlf, MCFD2, and ergic53 interacts with rotenone exposure contributing
to variation in PD-like phenotypes severity and progression. Finally, we will determine whether the Dorsal/NFκB protein interacts with the transcription factor binding site located upstream of dMlf and in the third intron
of dMCFD2 and whether gene-pesticide exposure interaction candidate alleles and rotenone exposure affect
this interaction.
Uncovering the molecular mechanisms by which non-coding variants modify the effects of pesticides, leading
to increased PD risk, severity, and progression, and the cellular context where these mechanisms operate
will contribute to understanding PD at the organism level and the design of personalized new therapeutic
strategies aimed at reducing the risk and severity and progression of the disease in individuals exposed to
pesticides
Keywords
Fields of Science and Technology (OECD)
Natural sciences
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