Parkinson’s Disease is a chronic progressive neurodegenerative disease that
affects approximately 2000 out of 100 000 people over the age of 80. This disease is
typically characterized by impaired motor function, as well as cognitive and autonomic
dysfunction as the pathology worsens. The two main hallmarks typically associated with
PD are the dopaminergic loss in the nigrostriatal pathway and the presence of Lewy
bodies. However, a cellular dysfunction has been commonly found in neurodegenerative
diseases, known as the hyperactivation of the Cdk5/p25 complex. This complex is an
essential target to focus on the protection of neurons and prevent the pathology of PD to
worsen as treatments are currently only temporary in symptom relief. Truncated Peptide 5
(TP5) is a Cdk5/p25 inhibitor that has demonstrated potential therapeutic effects in
neurodegenerative disease models such as Alzheimer’s Disease. Paraquat is an herbicide
that has implicated Parkinson’s Disease symptoms in those who have been exposed to
this toxin. The purpose of this study was to explore TP5’s therapeutic effects to determine
if TP5 has the potential drug to treat towards PD. TP5 was tested in vitro and in vivo
models that are exposed to paraquat to induce Parkinson’s Disease like phenotypes and
biochemical features. A truncated fragment of TP5, known as Peptide A, was also further
explored to determine potential therapeutic effects like TP5. TP5 has shown its ability to
protect differentiated SH-SY5Y cells and the dopaminergic morphology and behaviour of
C. elegans when exposed to paraquat. These results further support that TP5 has
neuroprotective effects against models of Parkinson’s Disease. TP5 was also able to
regulate the physiological mechanism of Cdk5, such as neurite outgrowth, to further understand its relationship with Cdk5 activity. Lastly, TP5 restored dopaminergic
morphology against worms exposed to paraquat. These results suggest TP5 influences the
pathology of PD, in both neuroprotective and neurorestorative manner, to confirm that
TP5’s potential as a therapeutic drug for Parkinson’s Disease. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24966 |
| Date | January 2019 |
| Creators | Tran, Judith |
| Contributors | Mishra, Ram, Neuroscience |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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