LRRK2 and Environmental Effects on Dopamine Systems within the Gut-Brain Axis: A Parkinson’s Disease Pathology Focus Restricted; Files Only

Bandlamudi, Shreya (Spring 2021)

Permanent URL: https://etd.library.emory.edu/concern/etds/02870x04m?locale=en
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Abstract

Parkinson’s disease (PD) is progressive, neurodegenerative disorder characterized by dopaminergic neuron degeneration in the susbtantia nigra pars compacta (SNpc) region of the midbrain, gut dysregulatory symptoms, and dopamine pathway dysregulation. Although the causes of PD are unknown, about ~5% of causes are attributable to genetic mutations, the most common being the G2019S mutation of the LRRK2 (Leucine Rich Repeat Kinase 2) gene, which is known to contribute to the development of inflammatory phenotypes. An overwhelming majority of PD diagnoses are due to a combination of genetic and environmental risk factors. Among these, a known environmental risk factor for PD includes pyrethroid pesticide exposure which is known to have negative neuroregulatory effects. This project seeks to explore the effects of environmental exposure to pesticides combined with genetic predisposition to PD in the LRRK2 genotypic background on dopamine systems within the brain and gut. We looked at experimental groups of mice treated with pesticide exposure or vehicle controls who either overexpressed the mutant form of LRRK2 (G2019S), overexpressed the wildtype form of LRRK2 (WTOE), or expressed wildtype LRRK2 (B6). In these mice, we analyzed dopaminergic neuron degeneration in the SNpc using stereology. We additionally looked in wildtype mice who were exposed to either pyrethroid pesticide or vehicle control for mRNA expression of dopamine-related genes, the LRRK2 gene, and cholinergic neurons (CHAT) as a marker of enteric function via qPCR in parts of the gut as well as in the SNpc and striatum.  There were no significant changes observed in numbers of dopaminergic neurons in the SNpc across treatment groups or genotypes, however this part of the study was significantly limited by its low power. We found increased expression of VMAT2 in the striatum of pyrethroid treated animals and decreased expression of CHAT and LRRK2 in the proximal large intestine of pyrethroid treated animals. Overall, our results need more powered analyses and further data to conclude that there are changes in dopamine systems due to LRRK2 mutation and environmental insult. However, the preliminary results provide groundwork into future analyses on the gut-brain connection of dopamine systems in eliciting PD pathology.

Table of Contents

Introduction and Background..................................................................1-10

Parkinson’s Disease: An Overview...................................................1-3

Dopamine Systems......................................................................3-4

The Gut-Brain Axis.....................................................................4-5

The Microbiome Connection...........................................................6-7

LRRK2....................................................................................7-9

Pyrethroid Pesticides...................................................................9-10

Objective and Project Questions.................................................................11

Specific Aims and Methods..................................................................12-16

Figures and Results.............................................................................17-24

Discussion and Future Directions............................................................25-30

List of Figures...................................................................................31-32

References.......................................................................................33-35 

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