Comparison of two models of GRN-deficiency using quantitative proteomics Pubblico

Abstract

Mutations in the gene Granulin (GRN) reduce levels of progranulin (PGRN) and result in the neurodegenerative diseases frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis. PGRN has been implicated in high level functions like neurite outgrowth, neuronal survival, and inflammation while its molecular function is hypothesized to occur in the lysosome. Accordingly, GRN is highly expressed in neurons and microglia. GRN-deficiency is marked by increased inflammation, lysosome dysfunction, and recently, dysfunction in lipid metabolism and catabolism. Various models are used to study these different features of GRN-deficiency. Here, I compare proteomic datasets from Grn WT and KO mouse embryonic fibroblasts (MEFs) and GRN WT and KO induced pluripotent stem cell-derived microglia (iPSC-microglia). Despite little overlap of proteins significant in both cell types, several pathways are significantly overrepresented in multiple genotype/cell model combinations like pathways containing “organelle” and “cellular response to stress.” Additionally, each subset identifies unique features of GRN-pathology, and each cell type offers protein targets to pursue. Overall, these analyses support the hypothesis that GRN pathology is driven by dysfunction in lysosomal lipid metabolism and catabolism resulting in the accumulation of lipids. Altogether, these analyses identify unique features of GRN-deficiency and support the use of MEFs as a model to study lipid accumulation in FTD and iPSC-microglia as a model for studying inflammation and possibly lipid droplet formation in FTD.

Table of Contents

Contents

Introduction. 7

Results. 8

Data Imputation. 8

Differential Expression Analysis 10

Pathway Overrepresentation Analysis. 11

Conclusion. 19

Methods. 24

Figures

Figure 1........................................................................................................................................... 28

Figure 2........................................................................................................................................... 28

Figure 3........................................................................................................................................... 29

Figure 4........................................................................................................................................... 29

Figure 5........................................................................................................................................... 30

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Figure 10......................................................................................................................................... 33

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Figure 13......................................................................................................................................... 34

 

Tables

Table 1. 35

Table 2. 36

Table 3. 37

 

Supplemental Figures

Supplemental Figure 1. 38

 

Supplemental Tables

Supplemental Table 1. 39

About this Master's Thesis

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Biology, Bioinformatics Biology, Neuroscience Biology, Biostatistics
Parola chiave	random forest granulin lipid induced pluripotent stem cell imputation frontotemporal dementia proteomic
Committee Chair / Thesis Advisor	Kukar, Thomas, Emory University Murphy, T.J., Emory University Hales, Chadwick, Emory University Hepler, John, Emory University

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