TSPO-VDAC complex as a regulator of microglial function

The translocator protein (TSPO) is a neuroinflammatory biomarker, upregulated in microglia in Alzheimer’s disease (AD) and potentially useful for diagnosis. Despite its potential application as a biomarker, little is known about the molecular functions underlying TSPO function in neuroin...

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Main Author: Lai, Kei Onn
Other Authors: Anna Barron
Format: Thesis-Doctor of Philosophy
Language:English
Published: Nanyang Technological University 2023
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Online Access:https://hdl.handle.net/10356/169980
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1699802023-09-04T07:32:08Z TSPO-VDAC complex as a regulator of microglial function Lai, Kei Onn Anna Barron Lee Kong Chian School of Medicine (LKCMedicine) barron@ntu.edu.sg Science::Biological sciences::Molecular biology The translocator protein (TSPO) is a neuroinflammatory biomarker, upregulated in microglia in Alzheimer’s disease (AD) and potentially useful for diagnosis. Despite its potential application as a biomarker, little is known about the molecular functions underlying TSPO function in neuroinflammation. Using transcriptomics and proteomics approaches, I found TSPO deletion to be associated with changes in mitochondrial bioenergetic and phagocytosis pathways in AD-related neuroinflammation. Microglial phagocytosis is an important protective function, clearing amyloid aggregates and preventing AD pathogenesis. In cultured microglia, I found that absence of TSPO impaired phagocytosis, underpinned by reduced actin polymerization, which is energetically demanding and critical for phagocytosis. TSPO directly binds VDAC(Voltage-dependent Anion Channel), which is a metabolic hub binding the glycolytic enzyme, Hexokinase (HK). I hypothesized that TSPO integrates microglia metabolism and phagocytosis through VDAC phosphorylation to regulate mitochondrial HK binding. In TSPO deficient microglia, I found HK enrichment at the mitochondria, while displacement of mitochondrial HK improved the phagocytic efficiencies. Finally, I show that the TSPO-VDAC complex regulates mitochondrial-cytoskeletal dynamics via VDAC interaction with Actin related protein 2(Arp2). Taken together, I propose that TSPO-VDAC complex are involved in regulating the microglial immunometabolic response in phagocytosis. Doctor of Philosophy 2023-08-21T08:27:27Z 2023-08-21T08:27:27Z 2022 Thesis-Doctor of Philosophy Lai, K. O. (2022). TSPO-VDAC complex as a regulator of microglial function. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/169980 https://hdl.handle.net/10356/169980 10.32657/10356/169980 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences::Molecular biology
spellingShingle Science::Biological sciences::Molecular biology
Lai, Kei Onn
TSPO-VDAC complex as a regulator of microglial function
description The translocator protein (TSPO) is a neuroinflammatory biomarker, upregulated in microglia in Alzheimer’s disease (AD) and potentially useful for diagnosis. Despite its potential application as a biomarker, little is known about the molecular functions underlying TSPO function in neuroinflammation. Using transcriptomics and proteomics approaches, I found TSPO deletion to be associated with changes in mitochondrial bioenergetic and phagocytosis pathways in AD-related neuroinflammation. Microglial phagocytosis is an important protective function, clearing amyloid aggregates and preventing AD pathogenesis. In cultured microglia, I found that absence of TSPO impaired phagocytosis, underpinned by reduced actin polymerization, which is energetically demanding and critical for phagocytosis. TSPO directly binds VDAC(Voltage-dependent Anion Channel), which is a metabolic hub binding the glycolytic enzyme, Hexokinase (HK). I hypothesized that TSPO integrates microglia metabolism and phagocytosis through VDAC phosphorylation to regulate mitochondrial HK binding. In TSPO deficient microglia, I found HK enrichment at the mitochondria, while displacement of mitochondrial HK improved the phagocytic efficiencies. Finally, I show that the TSPO-VDAC complex regulates mitochondrial-cytoskeletal dynamics via VDAC interaction with Actin related protein 2(Arp2). Taken together, I propose that TSPO-VDAC complex are involved in regulating the microglial immunometabolic response in phagocytosis.
author2 Anna Barron
author_facet Anna Barron
Lai, Kei Onn
format Thesis-Doctor of Philosophy
author Lai, Kei Onn
author_sort Lai, Kei Onn
title TSPO-VDAC complex as a regulator of microglial function
title_short TSPO-VDAC complex as a regulator of microglial function
title_full TSPO-VDAC complex as a regulator of microglial function
title_fullStr TSPO-VDAC complex as a regulator of microglial function
title_full_unstemmed TSPO-VDAC complex as a regulator of microglial function
title_sort tspo-vdac complex as a regulator of microglial function
publisher Nanyang Technological University
publishDate 2023
url https://hdl.handle.net/10356/169980
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