Thesis Format
Monograph
Degree
Master of Science
Program
Neuroscience
Supervisor
Pasternak, Stephen
Abstract
Parkinson's Disease (PD) and Dementia with Lewy Body (DLB) are neurodegenerative disorders characterized by the accumulation and aggregation of α-synuclein (α-syn) into Lewy Bodies, resulting in neuronal dysfunction and cell death. Beta-amyloid (Aβ), an Alzheimer’s Disease protein, is associated with accelerated dementia progression in DLB, and it could be an important feature distinguishing PD from DLB. However, the interactions of Aβ and α-syn remain unclear. Aβ42 oligomers (Aβ42o) are known to impair parts of the autophagy-lysosomal pathway (ALP), a key mechanism for α-syn clearance. We hypothesized that Aβ42o disrupts ALP function, leading to α-syn accumulation and aggregation. In this study, we assess the impact of Aβ42o on ALP function and clearance of α-syn in N2a cells expressing human α-syn. Our findings reveal that Aβ42o hinders autophagosomal sequestration of α-syn and reduces its lysosomal accumulation. Poisoning autophagy could be an important mechanism leading to the deposition of α-syn. These findings contribute to understanding the mechanisms of disease initiation in PD and LBD, providing potential targets for therapeutic interventions.
Summary for Lay Audience
α-synuclein (α-syn) is a protein that helps neurons to communicate in the brain. However, in Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB) it forms into large aggregates called Lewy Bodies, which lead to brain cell dysfunction and death. Recent studies have also identified the presence of beta-amyloid (Aβ), a protein linked to Alzheimer’s disease, in the brains of DLB patients, and some believe that Aβ makes α-syn pathology worse. Here we investigate the relationship between these two proteins. We suggest that Aβ might be poisoning the Autophagy-Lysosomal Pathway (ALP), a crucial system that normally behaves as a garbage disposal system in the cell getting rid of abnormal proteins. We studied this problem using a form of α-syn that we can attach a fluorescent dye to so that we can watch it under the microscope. Our findings revealed that the ALP is involved in α-syn clearance, as seen by the localization of α-syn in autophagosomes and lysosomes, compartments within the cell responsible for delivery and degradation. Next, we added Aβ to the cells and examined their impact on lysosomal function. Upon the Aβ treatment, we observed an increase in non-acidic lysosomes, indicating impaired lysosomal function. This dysfunction likely contributes to the reduced ability of lysosomes to degrade α-syn. Finally, we assessed the effect of Aβ on α-syn clearance through the ALP. Our results showed that Aβ presence led to a decrease in α-syn within lysosomes and autophagosomes, suggesting that Aβ impairs the cell's ability to clear α-syn effectively via this pathway. These findings enhance our understanding of how Aβ may contribute to the progression of PD and DLB by disrupting the clearance of α-syn, offering potential targets for therapeutic intervention.
Recommended Citation
Romadina, Diana, "The Effects of Amyloid-Beta 42 Oligomers on Alpha-synuclein Clearance" (2024). Electronic Thesis and Dissertation Repository. 10577.
https://ir.lib.uwo.ca/etd/10577
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
