Targeting of alpha-synuclein aggregates by the ubiquitin-proteasome system
File(s)
Author(s)
Sirvio, Liina
Type
Thesis
Abstract
The progressive accumulation of misfolded proteins into insoluble aggregate structures is a common hallmark of neurodegenerative disorders. In a subset of neurodegenerative disorders, the α-synucleinopathies, the main constituent of these aggregates is α-synuclein. Ineffective targeting of α-synuclein aggregates by cellular degradation pathways such as the ubiquitin-proteasome system may play a role in disease pathogenesis. Therefore, uncovering how α-synuclein aggregate forms may be targeted by cellular degradation pathways, could have therapeutic implications for these diseases. In this thesis, I have identified and characterised a novel cellular mechanism for the ubiquitin-proteasome system to target exogenously applied α-synuclein aggregates, wherein proteasomes redistribute into foci. I demonstrate that these foci are distinct from other known proteasome foci types in their size, duration, localisation, and physical properties. I suggest that other enzymes of the UPS and additional cofactors are also recruited to these foci, likely to assist proteasomes in aggregate disassembly and degradation. I further show that these novel foci could be induced by α-synucleinopathy patient-derived aggregates, and in neuronal-like cells, highlighting the potential relevance of this proteasomal response to neurodegenerative disorders. I also speculate that these foci may not be reversible in neurodegenerative disease states, resulting in disruption to cellular proteostasis and potentially contributing to disease progression. Overall, the data presented in this thesis has identified a new cellular mechanism through which αS aggregates may be targeted for proteasomal degradation and highlights the requirement to further investigate this novel proteasomal response.
Version
Open Access
Date Issued
2024-06-10
Date Awarded
01/10/2024
License URL
Advisor
Ye, Yu
Gentleman, Steve
Publisher Department
Department of Brain Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)