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The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson’s disease

Sandra L. Castro, Emily M. Rocha, Christopher R. Bodle, Katrina E. Johnson, J. Timothy Greenamyre, Briana R. De Miranda
doi: https://doi.org/10.1101/2020.11.02.365775
Sandra L. Castro
1Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Emily M. Rocha
1Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Christopher R. Bodle
1Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Katrina E. Johnson
1Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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J. Timothy Greenamyre
1Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Briana R. De Miranda
1Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • For correspondence: BrianaDeMiranda@uabmc.edu
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Abstract

Gene-environment interaction is implicated in the majority of idiopathic Parkinson’s disease (PD) risk, and some of the most widespread environmental contaminants are selectively toxic to dopaminergic neurons. Pesticides have long been connected to PD incidence, however, it has become increasingly apparent that other industrial byproducts likely influence neurodegeneration. For example, organic solvents, which are used in chemical, machining, and dry-cleaning industries, are of growing concern, as decades of solvent use and their effluence into the environment has contaminated much of the world’s groundwater and soil. Like some pesticides, certain organic solvents, such as the chlorinated halocarbon trichloroethylene (TCE), are mitochondrial toxicants, which are collectively implicated in the pathogenesis of dopaminergic neurodegeneration. Recently, we hypothesized a possible gene-environment interaction may occur between environmental mitochondrial toxicants and the protein kinase LRRK2, mutations of which are the most common genetic cause of familial and sporadic PD. In addition, emerging data suggests that elevated wildtype LRRK2 kinase activity also contributes to the pathogenesis of idiopathic PD. To this end, we investigated whether chronic, systemic TCE exposure (200 mg/kg) in aged rats produced wildtype LRRK2 activation and influenced predegenerative dopaminergic dysfunction. Interestingly, we found that TCE not only induced LRRK2 kinase activity in the brain, but produced a significant dopaminergic lesion in the nigrostriatal tract, elevated oxidative stress, and caused endolysosomal dysfunction and protein accumulation (α-synuclein). Together, these data suggest that TCE-induced LRRK2 kinase activity contributed to the selective toxicity of dopaminergic neurons. We conclude that gene-environment interactions between certain industrial contaminants and LRRK2 likely influence PD risk.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Omitted methods are now included, graph axes fixed in Figure 5.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 06, 2020.
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The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson’s disease
Sandra L. Castro, Emily M. Rocha, Christopher R. Bodle, Katrina E. Johnson, J. Timothy Greenamyre, Briana R. De Miranda
bioRxiv 2020.11.02.365775; doi: https://doi.org/10.1101/2020.11.02.365775
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The industrial solvent trichloroethylene induces LRRK2 kinase activity and dopaminergic neurodegeneration in a rat model of Parkinson’s disease
Sandra L. Castro, Emily M. Rocha, Christopher R. Bodle, Katrina E. Johnson, J. Timothy Greenamyre, Briana R. De Miranda
bioRxiv 2020.11.02.365775; doi: https://doi.org/10.1101/2020.11.02.365775

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