Broad Street Scientific Journal 2020

SMALL MOLECULE ACTIVATION OF
WNT/ β-CATENIN SIGNALING PATHWAY ON
NEURODEGENERATION RATES OF DOPAMINERGIC
NEURONS IN C. ELEGANS
Ariba Huda
Abstract
Parkinson’s Disease (PD) is a neurodegenerative disease characterized by loss of midbrain dopaminergic (mDA) neurons.
While there are several medical treatments available for PD, they often come with significant side effects and do not act
as definite cures. Past studies have indicated that Wnt/β-Catenin signaling is critical for the generation of dopamine
(DA) neurons during development and for further neurorepair. This study investigates the roles of small molecules,
Wnt Agonist 1 and Pyrvinium, in Wnt signaling and their effects on neurodegeneration. Wnt signaling was modeled
by Caenorhabditis Elegans (C. elegans), nematodes that display dopamine-dependent behavior in response to neurodegeneration.
24 hour exposure to Wnt Agonist 1 has been shown to significantly reduce neurodegeneration as observed
through locomotor behavior and chemotaxation. Currently, work is being done to measure BAR-1 and other Wnt related
ortholog gene expression within Wnt Agonist 1 exposed worms. Analysis of the functions behind the Wnt/β-Catenin
signaling pathway in the generation and neurorepair of mDA neurons will allow further understanding of the potential
for PD stem cell therapies.
1. Introduction
1.1 – Parkinson’s Disease
Parkinson’s Disease (PD) is a neurodegenerative disease
that results from the progressive cell death of dopaminergic
(DA) neurons. Currently, various medications
are prescribed to patients to control symptoms such as
cognitive decline and loss of motor function, but there is
no definitive cure. The most common therapy is the drug
levodopa (L-DOPA), which is used to stimulate dopamine
production in neurons associated with motor skill. However,
while L-DOPA is efficient at managing the extent
of symptoms, it also has various side effects on patients,
ranging from physiological to psychological. At present,
research is being conducted to identify the clinical applications
of stem cell therapy in Parkinson’s Disease as well as
the genetic factors behind PD [1]. These discoveries could
contribute to the development of a new therapy option
geared towards reducing the adverse effects of medications
on diagnosed patients.
Dopamine neurons are located in the human nigrostriatal
pathway, a brain circuit that connects neurons in the
substantia nigra pars compacta with the dorsal striatum.
Despite lack of a specific cause for neuronal loss, DA neuron
loss has been linked to genetic mutations and environmental
toxins [2]. Studies have shown that DA neurons
have a distinctive phenotype that could contribute to their
vulnerability. An example of this is the opening of L-type
calcium channels, which results in elevated mitochondrial
oxidant stress and susceptibility to toxins [2]. Moreover,
DA neurons are susceptible to degeneration because of
extensive branching and amounts of energy required to
transmit nerve signals along these branches [3].
1.2 – Wnt/β-Catenin Signaling Pathway
Due to the significance of the Wnt signaling pathway
for the healthy functioning of the adult brain, dysregulation
of these pathways in neurodegenerative disease has
become notable. Wnt/β-Catenin signaling is also critical
for the generation of DA neurons in embryonic stem cells
[4]. Since several of the biological functions disrupted in
PD are partially controlled by Wnt signaling pathways,
there is potential for therapy centered around targeting
these pathways [4].
In an activated state, Wnt proteins act as extracellular
signaling molecules that activate the Frizzled receptor.
Following the activation of Frizzled, the LRP receptor undergoes
phosphorylation, inducing the translocation of the
destruction complex, a complex of proteins that degrades
β-catenin, to the region of membrane near the two receptors
(Fig. 1). The activated dishevelled (Dsh) proteins cause
the inhibition of the destruction complex which prevents
β-catenin phosphorylation. Overall, an activated state of
the Wnt/β-Catenin signaling pathway causes an increase
in β-Catenin levels.
The transcription factor TCF mediates the genetic action
of Wnt signaling patterns, leading to the induction
of Wnt targeted genes. When β-Catenin levels increase,
they are translocated to the mitochondria, dislodging the
Groucho protein from TCF, and binding to TCF leading
to the transcription of Wnt targeted genes. The expressed
genes regulate cellular growth and proliferation. Without
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