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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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 |
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Science::Biological sciences::Molecular biology Lai, Kei Onn TSPO-VDAC complex as a regulator of microglial function |
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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. |
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Anna Barron |
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Anna Barron Lai, Kei Onn |
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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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1779156652766789632 |