Comparison of two models of GRN-deficiency using quantitative proteomics 公开
Nuckols, Thomas (Spring 2022)
Published
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
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Figure 10......................................................................................................................................... 33
Figure 11......................................................................................................................................... 33
Figure 12......................................................................................................................................... 34
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
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