42
IRUS Total
Downloads
  Altmetric

Immunoproteasomes in microglial activation and inflammation

File Description SizeFormat 
PulgarPrieto-K-2023-MPhil-Thesis.pdfThesis2.01 MBAdobe PDFView/Open
Title: Immunoproteasomes in microglial activation and inflammation
Authors: Pulgar Prieto, Katiuska Daniela
Item Type: Thesis or dissertation
Abstract: Chronic neuroinflammation and aggregation of misfolded proteins, like tau or α-synuclein, are distinctive features of neurodegenerative disorders. The ubiquitin-proteasome system (UPS) has been shown to be directly involved in the degradation of aggregates, as well as in sustaining inflammation in Alzheimer’s disease. Pro-inflammatory stimuli, such as cytokines, are known to upregulate proteasomal subunits which presumably lead to enhanced degradation. However, the exact role of the UPS in regulating inflammatory responses is not well understood. This MPhil project mainly focuses on the underlying mechanisms of the UPS in microglia, which are suspected to lead to chronic inflammation in neurodegenerative disorders. I am especially interested in the distinct functions of the standard (sP) versus the immuno- proteasome (iP) in regulating pro-inflammatory signaling in the NF-kB and c/EBPb pathways. I performed advanced fluorescence imaging on iPSC-derived microglia stimulated with TNF- α, IFN-γ or LPS. Intriguingly, my preliminary results in microglia suggested that both the sP and the iP are upregulated upon stimulation, with different localization patterns. This indicates that the sPs and iPs may carry out distinct roles in response to external stimuli. I further tested how proteasomes responded to aggregate stimuli in cell lines already established in our lab, and found that proteasomes accumulated around invading aggregates, forming foci in a cytoskeleton-dependent manner. The next stage of this research would be to study sPs and iPs in microglia differentiated from patient-derived iPSCs, and how their relative ratio and activities regulate distinct inflammatory pathways. Revealing the individual functions of the sPs versus the iPs will unveil novel targets for therapeutic intervention against overactive microglia.
Content Version: Open Access
Issue Date: Aug-2022
Date Awarded: Mar-2023
URI: http://hdl.handle.net/10044/1/103995
DOI: https://doi.org/10.25560/103995
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Ye, Yu
Thomas, David
Sponsor/Funder: Imperial College London
Department: Department of Brain Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Master of Philosophy (MPhil)
Appears in Collections:Department of Brain Sciences PhD Theses



This item is licensed under a Creative Commons License Creative Commons