Does the activity of the proteasome decline during human ageing and in the brains of Parkinson’s disease patients?

Wayne, Declan (2018) Does the activity of the proteasome decline during human ageing and in the brains of Parkinson’s disease patients? MRes thesis, University of Nottingham.

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Background: It is well documented that the global population is steadily rising. A major factor for the rising population is the increase in life expectancy. As medical advancements are, made we are now living longer than at any point in human history. As a result of this, levels of neurodegeneration are at an all-time high and propose a significant health burden. Parkinson ’s disease (PD) is the world’s second most prevalent neurodegenerative disease, which has its pathology linked to a range of complex interactions resulting in accumulation of protein aggregates, increased cellular oxidative stress, impaired mitochondrial function and dysfunction within the cellular maintenance systems, the ubiquitin proteasome system (UPS) and the lysosomal degradation pathway. This project aims to assess potential decline in UPS activity in PD and in conventional ageing, whilst also investigating dysregulation of important homeostatic cellular proteins as a result of oxidative stress.

Method: Post-mortem PD (n=11) and Control (n=10) brain tissue samples, alongside an ageing study group (n=40 23 years-93 years) underwent a fluorometric analysis of UPS activity utilising the fluorogenic substrate n-succinyl-leu-leu-val-tyr-7-amido-4-methylcoumarin targeting the 20S proteasome chromotrypsin-like activity in seven different brain regions instigated in the pathology of PD. Western blot analysis of the ageing study group targeting proteins impacted in oxidative stress; SOD1, alpha tubulin and beta tubulin.

Results: The UPS activity assay suggests that there is no significant change within any region assessed within PD/control samples and in the ageing brain (p=>0.05 in all cases). We noted a significant decrease in a range of integral cellular proteins in the ageing study, as SOD1, alpha and beta tubulin all showed visual decline. However, only alpha tubulin decline was statistically significant (p=0.0206).

Interpretation: The lack of change within the rate of 20S proteasome activity in PD or in ageing within any assessed region suggests that there may be a more fundamental underlying cause for the decrease in UPS activity within PD that was not assessed within this study. The overall decrease in SOD1 and alpha and beta tubulin are indicative of an increased level of oxidative damage within ageing cells. Reduced levels of these proteins can lead to significant cellular stress, impacting the levels of oxidative stress within the intracellular environment and functionality of the autophagy-lysosomal pathway.

Item Type: Thesis (University of Nottingham only) (MRes)
Supervisors: Carter, Wayne
Szewczyk, Nate
Keywords: Neurodegeneration, Ubiquitin Proteasome System, Parkinson's Disease.
Subjects: W Medicine and related subjects (NLM Classification) > WL Nervous system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 55407
Depositing User: Wayne, Declan
Date Deposited: 01 Aug 2019 11:50
Last Modified: 07 May 2020 11:02

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