Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages

Lienden, Martijn J.C. van der; Gaspar, Paulo; Boot, Rolf G.; Aerts, Johannes M. F. G.; Eijk, Marco van

doi:10.3390/ijms20010066

Cited by 63 publications

(54 citation statements)

References 187 publications

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“…Progranulin deficiency reduces glucocerebrosidase activity [ 116 , 134 ] suggesting that the accumulation of glucosylceramide or other sphingolipids could be a proximal cause of GPNMB upregulation in the Grn −/− mouse brain, an idea that needs further investigation. Although the precise mechanism that causes GPNMB upregulation in progranulin deficiency is unclear, our data suggest that measurement of GPNMB levels in the CSF could be used to monitor changes in microglial activation and response to therapies in FTD- GRN patients, similar to substrate reduction therapy in lysosome storage disorders [ 71 , 78 , 119 ]. One limitation of our data is a small sample size and lack of longitundal testing.…”

Section: Discussionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn+/+) and Grn knockout (Grn−/−) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn−/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn−/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn−/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD-GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn−/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD-GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD-GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies.

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Section: Discussionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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“…GPNMB (glycoprotein nonmetastatic melanoma protein B) (also called osteoactivin) is a single-pass transmembrane protein that in upregulated by both lysosomal stress and inhibition of mTORC1 (Gabriel et al 2014). GPNMB is a regulator of melanosome formation and protein degradation pathways (van der Lienden et al 2018) and inhibits inflammation (Neal et al 2018) and amyloid formation (Yang et al 2018). Increases in GPNMB mRNA were measured in lumbar spinal cord of SOD1 G93A mice and GPNMB protein was increased in CSF of sporadic ALS (Tanaka et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS

Zhu

Wuolikainen

et al. 2019

J Mol Neurosci

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The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) share some common molecular deficits including disruption of protein homeostasis leading to disease-specific protein aggregation. While insoluble protein aggregates are the defining pathological confirmation of diagnosis, patient stratification based on early molecular etiologies may identify distinct subgroups within a clinical diagnosis that would respond differently in therapeutic development programs. We are developing targeted multiple reaction monitoring (MRM) mass spectrometry methods to rigorously quantify CSF proteins from known disease genes involved in lysosomal, ubiquitin-proteasomal, and autophagy pathways. Analysis of CSF from 21 PD, 21 ALS, and 25 control patients, rigorously matched for gender, age, and age of sample, revealed significant changes in peptide levels between PD, ALS, and control. In patients with PD, levels of two peptides for chromogranin B (CHGB, secretogranin 1) were significantly reduced. In CSF of patients with ALS, levels of two peptides from ubiquitin carboxy-terminal hydrolase like protein 1 (UCHL1) and one peptide each for glycoprotein non-metastatic melanoma protein B (GPNMB) and cathepsin D (CTSD) were all increased. Analysis of patients with ALS separated into two groups based on length of survival after CSF sampling revealed that the increases in GPNMB and UCHL1 were specific for short-lived ALS patients. While analysis of additional cohorts is required to validate these candidate biomarkers, this study suggests methods for stratification of ALS patients for clinical trials and identifies targets for drug efficacy measurements during therapeutic development.Electronic supplementary materialThe online version of this article (10.1007/s12031-019-01411-y) contains supplementary material, which is available to authorized users.

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“…Gpnmb expression is increased in foam cells[4, 10], especially M2 polarized macrophages[11]. This GPNMB protein is also induced in lysosomal storage diseases[12]. We now describe our findings that the Gpnmb gene is responsible for the Mlfm1 QTL.…”

Section: Introductionmentioning

confidence: 82%

“…Gpnmb encodes for Glycoprotein Non-Metastatic Protein B (GPNMB) which was originally discovered in a melanoma cell line[21]. This protein, also called osteoactivin, DC-HIL, or hematopoietic growth factor inducible neurokinin-1, has been studied extensively in many contexts including cancer, kidney injury, obesity, non-alcoholic steatohepatitis, Parkinson disease, osteoarthritis, lysosome storage disorders, and heart failure; and, in most of these contexts expression of GPNMB is induced by the related pathology, likely in response to lysosomal stress[12, 22–27]. However, loss of Gpnmb expression in DBA/2J mice is associated with preserved cardiac function after myocardial infarction[28].…”

Section: Discussionmentioning

confidence: 99%

QTL analysis of macrophages from an AKR/JxDBA/2J intercross identified the Gpnmb gene as a modifier of lysosome function

Robinet

Ritchey

Alzayed

et al. 2019

Preprint

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Our prior studies found differences in the AKR/J and DBA/2J strains in regard to atherosclerosis and macrophage phenotypes including cholesterol ester loading, cholesterol efflux, and autolysosome formation. The goal of this study was to determine if there were differences in macrophage lysosome function, and if so to use quantitative trait locus (QTL) analysis to identify the causal gene. Lysosome function was measured by incubation with an exogenous double-labeled ovalbumin indicator sensitive to proteolysis. DBA/2J vs. AKR/J bone marrow macrophages had significantly decreased lysosome function. Macrophages were cultured from 120 mice derived from an AKR/JxDBA/2J F4 intercross. We measured lysosome function and performed a high density genome scan. QTL analysis yielded two genome wide significant loci on chromosomes 6 and 17, called macrophage lysosome function modifier (Mlfm) loci Mlfm1 and Mlfm2. After adjusting for Mlfm1, two additional loci were identified. Based on proximity to the Mlfm1 peak, macrophage mRNA expression differences with AKR/J >> DBA/2J, and a protein coding nonsense variant in DBA/2J, the Gpnmb gene, encoding a lysosomal membrane protein, was our top candidate. To test this candidate, Gpnmb expression was knocked down with siRNA in AKR/J macrophages; and, to express the wildtype Gpnmb in DBA/2J macrophages, we obtained a DBA/2 substrain, DBA/2J-Gpnmb+/SjJ, which was isolated from the parental strain prior to its acquiring the nonsense mutation, and subsequently back crossed to the modern DBA/2J background. Knockdown of Gpnmb in AKR/J macrophages decreased lysosome function, while restoration of the wildtype Gpnmb allele in DBA/2J macrophages increased lysosome function. However, this modifier of lysosome function was not responsible for the strain differences in macrophage cholesterol ester loading or cholesterol efflux. In conclusion, we identified the Gpnmb gene as the major modifier of lysosome function and we showed that the ‘QTL in a dish’ strategy is efficient in identifying modifier genes.Author SummaryInbred strains of mice differ in both their genetic backgrounds as well as in many traits; and, classical mouse genetics allows the mapping of genes responsible for these traits. We identified many traits that differ between the inbred strains AKR/J and DBA/2J, including atherosclerosis susceptibility, macrophage cholesterol metabolism, and in the current study, macrophage protein degradation via an organelle called the lysosome. Using mouse genetic mapping and bioinformatics we identified a candidate gene, called Gpnmb, responsible for modifying lysosome function; and, the DBA/2J strain carries a mutation in this gene. Here we demonstrate that the Gpnmb gene is a modifier of lysosome function by either correcting this Gpnmb mutation in DBA/2J macrophages, or by knocking down Gpnmb expression in AKR/J macrophages. This study is noteworthy as the human GPNMB gene has been implicated in many diseases including cancer, kidney injury, obesity, non-alcoholic steatohepatitis, Parkinson disease, osteoarthritis, and lysosome storage disorders.

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Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages

Cited by 63 publications

References 187 publications

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS

QTL analysis of macrophages from an AKR/JxDBA/2J intercross identified the Gpnmb gene as a modifier of lysosome function

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