The Use of a Novel Alpha-Synuclein Binding Aptamer in Models of Parkinson’s Disease

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Creator: 

Ventura, Katelyn Victoria

Date: 

2021

Abstract: 

Parkinson's disease (PD) is characterized by a range of motor and non-motor behavioral deficits thought to occur because of the loss of dopaminergic neurons in the substantia nigra. It has been thought that the appearance of the disorder stems from elevated alpha-synuclein (asyn) protein expression, known to form Lewy body inclusions. The overarching theme of the current series of experiments comprised the evaluation of how increased asyn expression contributes to the development of PD, and whether these actions could be attenuated by a DNA sequence designed to inhibit asyn oligomer formation. A better understanding of asyn protein accumulation and toxic aggregate formation might provide a therapeutic avenue with considerable clinical relevance, especially if tolerance does not develop as it does with other therapeutic approaches. As such, we assessed a novel asyn binding aptamer within both in vitro and in vivo models of Parkinson's disease. In vitro, a single treatment with the asyn aptamer reduced levels of pAsyn, but multiple treatments unexpectedly had less noteworthy effects. Accordingly, the influence of the asyn aptamer was assessed in mice in vivo. It was demonstrated that the aptamer could be detected in several brain regions and in the liver at various times following administration. Ordinarily, in transgenic mice overexpressing the human A53T variant of asyn protein, the elevated expression of asyn protein occurs at 5 months of age. Thus, transgenic mice of this age were treated with the asyn aptamer both acutely and repeatedly to detect asyn protein level changes. The aptamer reduced pAsyn levels compared to control wildtype animals. Indeed, Western blot analyses revealed that this was evident with respect to pAsyn and oligomer asyn in response to both acute and repeated treatment conditions. These reductions in asyn conformations were evident in the more exterior and interior regions of the brain. Overall, the data have important preliminary implications for the development of asyn aptamer treatment strategies that target asyn processes in PD. To be sure, the asyn aptamer needs to be assessed in other preclinically relevant models to determine the validity of the approach to halt or slow the progression of PD.

Subject: 

Neuroscience
Pharmacology
Mental Health

Language: 

English

Publisher: 

Carleton University

Contributor: 

Collaborator: 
Spencer Boisjoli
Collaborator: 
Vernon Hunt

Thesis Degree Name: 

Doctor of Philosophy: 
Ph.D.

Thesis Degree Level: 

Doctoral

Thesis Degree Discipline: 

Neuroscience

Parent Collection: 

Theses and Dissertations

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