Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia

Simon, Matthew; Logan, Todd; DeVos, Sarah L.

doi:10.1016/j.tcb.2022.09.006

Cited by 44 publications

(43 citation statements)

References 111 publications

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“…The KEGG analysis results suggest that the differential proteins in KO-d3 vs. WT-d3 group are mainly enriched in the “Lysosome.” These findings are consistent with previous results suggest that PGRN plays a critical role in regulating lysosome function, including proteolysis, lipid degradation, and lysosomal biogenesis ( Tayebi et al, 2020 ; Davis et al, 2021 ; Takahashi et al, 2021 ; Zhao et al, 2021 ; Simon et al, 2022 ). The enhanced activity and maturation of several cathepsins is reported in embryonic fibroblasts and aged brains from PGRN KO mice ( Gotzl et al, 2018 ), we also observed a significantly increased expression of CTSS and CTSA in influenza virus-infected lung tissues from PGRN KO mice.…”

Section: Discussionsupporting

confidence: 93%

Tandem mass tag-based quantitative proteomics analysis reveals the new regulatory mechanism of progranulin in influenza virus infection

Zhang

et al. 2023

Front. Microbiol.

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Progranulin (PGRN) plays an important role in influenza virus infection. To gain insight into the potential molecular mechanisms by which PGRN regulates influenza viral replication, proteomic analyzes of whole mouse lung tissue from wild-type (WT) versus (vs) PGRN knockout (KO) mice were performed to identify proteins regulated by the absence vs. presence of PGRN. Our results revealed that PGRN regulated the differential expression of ALOX15, CD14, CD5L, and FCER1g, etc., and also affected the lysosomal activity in influenza virus infection. Collectively these findings provide a panoramic view of proteomic changes resulting from loss of PGRN and thereby shedding light on the functions of PGRN in influenza virus infection.

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Section: Discussionsupporting

confidence: 93%

Tandem mass tag-based quantitative proteomics analysis reveals the new regulatory mechanism of progranulin in influenza virus infection

Zhang

et al. 2023

Front. Microbiol.

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“…As DQ‐BSA is a very unspecific substrate, changes in PRGN or PSAP would not be reflected in this assay. Furthermore, the question of how PRGN and PSAP impact the activity of other proteases is still under debate 53 . For instance, GRN (derived from PGRN) peptides stimulate Cathepsin D (CatD) activity in cell‐free assays 28 .…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the question of how PRGN and PSAP impact the activity of other proteases is still under debate. 53 For instance, GRN (derived from PGRN) peptides stimulate Cathepsin D (CatD) activity in cell-free assays. 28 However, several reports have shown that depending on the cell type; these peptides also inhibit cathepsin D activity.…”

Section: Cab45-deficient Cells Accumulate Perinuclear Lamp1-positive ...mentioning

confidence: 99%

Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning

Tran

Tüshaus

Kim

et al. 2023

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The trans-Golgi Network (TGN) sorts molecular "addresses" and sends newly synthesized proteins to their destination via vesicular transport carriers. Despite the functional significance of packaging processes at the TGN, the sorting of soluble proteins remains poorly understood. Recent research has shown that the Golgi resident protein Cab45 is a significant regulator of secretory cargo sorting at the TGN. Cab45 oligomerizes upon transient Ca 2+ influx, recruits soluble cargo molecules (clients), and packs them in sphingomyelin-rich transport carriers. However, the identity of client molecules packed into Cab45 vesicles is scarce. Therefore, we used a precise and highly efficient secretome analysis technology called hiSPECs. Intriguingly, we observed that Cab45 deficient cells manifest hypersecretion of lysosomal hydrolases. Specifically, Cab45 deficient cells secrete the unprocessed precursors of prosaposin (PSAP) and progranulin (PGRN). In addition, lysosomes in these cells show an aberrant perinuclear accumulation suggesting a new role of Cab45 in lysosomal positioning. This work uncovers a yet unknown function of Cab45 in regulating lysosomal function.

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“…These gene signatures were largely specific for tauopathy; however, we identified a number of lysosomal genes that were altered in iPSC-neurons from MAPT mutations and in brains from GRN mutation carriers. GRN has been implicated in lysosomal function and neuronal integrity ( Martens et al, 2012 ; Kao et al, 2017 ; Logan et al, 2021 ; Mohan et al, 2021 ; Simon et al, 2022 ). Thus, our stem cell model revealed several genes and pathways that are also altered in primary tauopathy patients.…”

Section: Discussionmentioning

confidence: 99%

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

Minaya

Mahali

Iyer

et al. 2023

Front. Mol. Biosci.

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Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau.Methods: We analyzed genes differentially expressed in induced pluripotent stem cell–derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

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Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia

Cited by 44 publications

References 111 publications

Tandem mass tag-based quantitative proteomics analysis reveals the new regulatory mechanism of progranulin in influenza virus infection

Tandem mass tag-based quantitative proteomics analysis reveals the new regulatory mechanism of progranulin in influenza virus infection

Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

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