Degree Type

Dissertation

Date of Award

2017

Degree Name

Doctor of Philosophy

Department

Theses & dissertations (Interdisciplinary)

Major

Immunobiology

First Advisor

Anumantha G. Kanthasamy

Abstract

Increasing evidence from epidemiological studies, retrospective studies, clinical observations

as well as pre-clinical in-vitro and in-vivo data suggest that Parkinson’s disease involves both

the enteric and central nervous system. Notably intestinal dysfunction along with anosmia is

one of the most common symptoms observed even decades before PD diagnosis. In order to

understand how intestinal inflammation affects the enteric nervous system in the context of

PD, we conducted multiple studies including a transgenic mouse model of PD (MitoPark), a

mouse model of chronic exposure to environmental toxin manganese (Mn) as well as a

known mouse model of intestinal inflammation-the dextran sodium sulfate (DSS) mouse

model of colitis. PD and indeed many neurological disorders are gradually being recognized

as multi-faceted maladies involving genetic predisposition and environmental triggers. Mn

exposure has been implicated in environmentally-linked PD as evidenced by epidemiological

studies done on humans exposed to Mn during mining, welding metals, and dry battery

manufacturing. With the prevalence of high Mn content in the groundwater in many regions

of US, we sought to elucidate the effect of chronic low-dose exposure to Mn on the GI tract.

We found that Mn does affect the ENS, particularly the enteric glial cells (EGC) inducing

mitochondrial dysfunction and ultimately cell death. In an in vivo model of chronic Mn

exposure, we observed that even a low dose of Mn was sufficient to decrease GI motility,

alter the gut microbiome population as well as GI metabolism. MitoPark mice that mimic the

adult-onset and progressive nature of PD showed mild intestinal inflammation and spatial

differences in gastrointestinal (GI) motility. Curiously, these mice have higher motility in the

small intestine but lower in the large intestine. Moreover, exposure to an environmental toxin

potentiated cell death in the colon with 12-week-old MitoPark having increased proapoptotic

protein bax compared to non-exposed transgenic controls. In older MitoPark mice,

the ENS showed presence of inflammation with increased expression of pro-inflammatory

factors – inducible nitric oxide (iNOS) and tumor necrosis factor alpha (TNFα). We also

found similar results in mice afflicted with DSS-induced colitis. These mice showed

intestinal inflammation as well as immune cell infiltrations. Intriguingly, the lumbosacral

region of the spinal cord and the substantia nigra region in the brain also showed higher proinflammatory

(TNFα, iNOS and IL-1β) transcripts. Taken together, the data suggests that

intestinal inflammation- caused either by a genetic predisposition or exposure to

environmental toxin- can induce neurochemical changes in the ENS and consequently

changes in the CNS via the gut-brain axis.

Copyright Owner

Shivani Ghaisas

Language

en

File Format

application/pdf

File Size

260 pages

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