Abstract
Parkinson’s disease (PD), characterized by the degeneration of dopaminergic (DA) neurons via -Synuclein (S)
aggregation, costs $51.9 billion annually in the US and is predicted to affect 1.2 million Americans by 2030.
Current treatments only provide limited and symptomatic relief, with no functional cure, largely due to the
mysterious nature in which PD is initiated. Thus, a deeper, mechanistic understanding of PD pathogenesis is vital
for effective treatment. An emerging hypothesis is that PD begins in the gut, where S aggregates spread from
the gut to the brain via routes like the vagus nerve. Interestingly, these S aggregates are detected in the gut years
before PD diagnosis. In addition, gut permeability and dysfunction are common in PD patients. Although these
intestinal pathologies likely lead to in the translocation of gut bacteria and microbe-associated molecular patterns
(MAMPs) into host tissues and subsequent induction of inflammation via innate immune receptor activation, this
has not been directly investigated. Thus, the role of gut bacteria and innate immune receptors in S aggregation
and PD progression is unclear. Furthermore, mammalian models for PD like mice are biologically complex,
harbor a diverse gut microbiota, and cannot undergo unbiased mutagenesis screens to identify novel PD factors.
Thus, a minimalist model which is genetically tractable and permits mutagenesis screens for both the host and
individual microbes would empower identification of novel host and bacterial factors crucial to PD pathogenesis.
To this end, I propose to use the nematode Caenorhabditis elegans, a model organism widely used in disease
study and PD research, to investigate how gut bacteria may trigger inflammatory responses that exacerbate
DA neurodegeneration. The particular model that I will use co-expresses human S and GFP in DA neurons,
causing a progressive loss of DA neurons as indicated by GFP signal loss. My proposed studies will use the
CRISPR-Cas9 genome editing technique to inactivate genes crucial for gut barrier integrity and innate immune
receptors and then investigate the spatial role of these genes in PD pathogenesis by monitoring fluorescently-
labeled S and GFP-labeled DA neurons. Furthermore, bacterial species or specific MAMPs will be individually
given to C. elegans as bacterial food sources or treatments, respectively, to identify what bacterial characteristics
may enhance or suppress PD. Lastly, I will conduct mutagenesis screens on C. elegans and individual bacterial
lawns to identify novel host and bacterial factors, respectively, which either promote or inhibit PD progression.
My proposed study will help identify novel therapeutic targets and treatments to block or potentially reverse PD,
using C. elegans as a cost-efficient screening tool. This project is highly interdisciplinary, combining
immunology, neurobiology, microbiology, enteric biology, and genetics. This strategy improves the possibility
of identifying novel factors and treatments which affect PD pathogenesis.
