Progranulin: at the interface of neurodegenerative and metabolic diseases

Nguyen, Andrew; Nguyen, Thi A.; Martens, Lauren Herl; Mitic, Laura L.; Farese, Robert V.

doi:10.1016/j.tem.2013.08.003

Cited by 76 publications

(76 citation statements)

References 92 publications

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“…This differential regulation is in line with the notion that most CSF progranulin is either brain-derived or actively transported from the vascular compartment into the CSF, as suggested by the high intrathecal fraction of CSF progranulin (80-90%) [38]. In contrast, progranulin levels in peripheral body tissues are subject to various other factors, such as systemic proliferation, metabolism and inflammation [40,41]. …”

Section: Discussionsupporting

confidence: 72%

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia

et al. 2016

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Background and Objective: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Methods: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Results: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Conclusions: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.

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Section: Discussionsupporting

confidence: 72%

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia

et al. 2016

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“…For example, the precursor to GRN is progranulin, and serves as the ligand for sortilin 1 (SORT1),45 which, in turn, is thought to regulate lipoprotein metabolism and has been linked to risk of myocardial infarction in previous genome‐wide association studies studies 46. We now demonstrate an association of GRN with both CVD and all‐cause mortality, supporting the association of the GRN/SORT1 pathway with CVD events.…”

Section: Discussionsupporting

confidence: 71%

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Lyass

Courchesne

et al. 2018

JAHA

211

228

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BackgroundThe discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk‐stratification methods and may be informative regarding biological pathways contributing to disease.Methods and ResultsWe used a discovery proteomic platform that targeted high‐value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable‐adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all‐cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P‐value ranges, 9.8×10−34 to 3.6×10−2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin‐like growth factor 1 (IGF1), insulin‐like growth factor binding protein 1 (IGFBP1), insulin‐like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N‐terminal pro‐b‐type natriuretic peptide, C‐reactive protein, and leptin were associated with incident heart failure, and C‐type lectin domain family 3 member B (CLEC3B; tetranectin), N‐terminal pro‐b‐type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin‐C were associated with all‐cause mortality in a multimarker model.ConclusionsWe identified numerous protein biomarkers that predicted cardiovascular outcomes and all‐cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention.

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“…Of note, its transcription is induced by transcription factor NF-jB, which is activated by TNFa, possibly explaining the concomitant reduction of these two cytokines. Moreover, both IL-15 and progranulin are protective towards obesity and insulin resistance (Nguyen et al, 2013;Ye, 2014), supporting the hypothesis that progranulin, TNFa and IL-15 are involved in a common biologic pathway.…”

Section: Discussionsupporting

confidence: 66%