CURES Seminar: "Identifying Novel Gene-Environmental Interactions in Parkinson's Disease"

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Date: October 31, 2019
Time: 12:30 p.m. - 1:30 p.m.
Location: Integrative Biosciences Center 1D
Category: Seminar

The Center for Urban Responses to Environmental Stressors (CURES) presents their Thursday afternoon serminar series on October 31, 2019 from 12:30 to 1:30 p.m. at the IBio Building in Seminar Room 1D, located at 6135 Woodward Ave.  The seminar is free and open to the entire University community.

The guest speaker will be Briana De Miranda, Ph.D., Postdoctoral Research Fellow of the Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh.  Dr. De Miranda will present "Identifying Novel Gene-Environmental Interactions in Parkinson's Disease".

Dr. De Miranda received both a Bachelors of Science (Biological Sciences) and a Doctorate (Toxicology) from Colorado State University, Fort Collins.  Her research focuses on the nexus between environmental toxicants and genetic susceptibility that increase risk for developing Parkinson's Disease. 


Environmental toxicants that cause mitchondrial dysfunction, such as the organic pesticide rotenone, and the common herbicide paraquat, are associated with elevated Parkinson's disease (PD) risk.  A heavily used industrial solvent, trichloroethylene (TCE), also causes mitochondrial toxicity, and is a ubiquitous environmental contaminant.  Occcupational TCE exposure is linked to the development of PD (odds ratio (OR): 6.1; 95% CI). Similarly, high doses (800-1,000 mg/kg) of TCE administration to rodents results in dopaminergic neurodegeneration.

New data from our lab indicates that rotenone, paraquat, and TCE interact with PD susceptibility genes, notably, causing the activation of the protein LRRK2 (leucine-rich repeat kinase 2) in wildtype human embryonic kidney (HEK) cells, which could be blocked by a selective LRRK2 inhibitor (PF-360).  As LRRK2 is the most commonly inherited mutation associated with familial PD, this evidence suggests that a gene-environment interaction exists between LRRK2 and common environmental mitchondrial toxicants. Aberrant LRRK2 activation leads to pleiotropic cellular dysfunction, such as disruption of vesicular trafficking and autophagy, accumulation of phosphorylated a-synuclein, and neuroinflammation; all of which are mechanisms hypothesized to precede dopaminergic neuron degeneration in PD.

As TCE is a widespread environmental contaminant, we postulated that relatively low levels of TCE exposure in aged rats may induce LRRK2 activation in dopaminergic neurons and increase risk of a parkinsonian phenotype.  Using adult, male Lewis rats (12 mo.) we administered 200 mg/kg of TCE (oral gavage) or vehicle (olive oil) daily for 6-weeks.  Animals receiving TCE displayed a moderate loss of dopaminergic neurons within the substantia nigra, which correlated with a significant increase in LRRK2 kinase activity in surviving cells.  In addition, we observed marked deficits in endolysosomal trafficking and function, concomitant with accumulation of toxic forms of a-synuclein (phosopho-Serine129) within dopaminergic neurons.  Together, these data suggest that LRRK2 activation by environmental TCE may be a novel gene-environment interaction, resulting in early pathological changes within susceptible indivdiuals to increase PD risk.


Christina Cowen




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