Protein interactomes of Alzheimer’s disease risk genes Abi3 and Trem2 in microglia-like cells

Widnall, Catherine 2022. Protein interactomes of Alzheimer’s disease risk genes Abi3 and Trem2 in microglia-like cells. PhD Thesis, School of Medicine, Cardiff University. Item availability restricted.

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most prevalent form of dementia. Over 50 genetic susceptibility loci have been identified for late onset AD, including coding variants in the ABI3 and TREM2 genes. The ABI3 protein is known to interact with the WAVE regulatory complex (WRC) which regulates actin cytoskeletal dynamics. By contrast, TREM2 is a membrane receptor, expressed by myeloid cells including microglia, that regulates many cellular functions including inflammatory responses and cytoskeletal remodelling. While genetic variants of ABI3 and TREM2 contribute to the genetic risk of AD, little is known about the function of these genes in microglia. Elucidating the interactome of these proteins provides a mechanistic insight into their role in microglia and can be used to explore the functional consequences of AD-associated genetic coding variants on molecular interactions. The proximity labelling technique BioID was used to determine the protein-protein interactions of Abi3, Abi3-S212F (mouse equivalent of the human risk variant p.S209F) and Trem2 in mouse BV2 microglia-like cells. Abi3 was found to interact with the WRC components Wasf2 and Cyfip1, demonstrating the efficacy of BioID for detecting interacting proteins. Several novel interactors, including the centrosomal protein Cep170, were also identified as components of the Abi3 interactome. Abi3-S212F interacted with several proteins found in the Abi3 interactome in addition to several unique interactors that were not associated with wild type Abi3. Quantitative differences were observed between shared components of the Abi3 and Abi3-S212F interactomes, potentially suggesting that Abi3-S212F may be more tightly associated with the WRC. Trem2 interactors mostly consisted of secretory and endosomal pathway proteins suggesting the life cycle of Trem2 from the endoplasmic reticulum/Golgi to the plasma membrane and receptor internalisation and recycling was captured. The data presented herein define the first protein interactomes for Abi3, Abi3-S212F, and Trem2 in disease-relevant cells, contributing to our understanding of the molecular mechanism of AD risk.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Date of First Compliant Deposit:	30 June 2023
Last Modified:	24 Jun 2024 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/160720

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