TP5: A POTENTIAL THERAPEUTIC DRUG FOR PARKINSON’S DISEASE

Abstract

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.