Further evidence for plasma progranulin as a biomarker in bipolar disorder

Kittel‐Schneider, Sarah; Weigl, Johannes; Volkert, Julia; Gessner, Alexandra; Schmidt, Brigitte; Hempel, Susanne; Kiel, Tilman; Olmes, David G.; Bartl, Jasmin; Weber, Heike; Kopf, Juliane; Reif, Andreas

doi:10.1016/j.jad.2014.01.006

Cited by 27 publications

(31 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years, GRN has emerged as a gene of interest in multiple neurodegenerative disorders including FTD, Alzheimer’s disease, and neuronal ceroid lipofuscinosis (NCL), as well as bipolar disorder (Cenik et al, 2012, Kittel-Schneider et al, 2014). Research into PGRN and its role in diverse aspects of CNS function with a clear causal role for haploinsufficiency in driving FTD makes it an attractive therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

She

Kurtser

Reis

et al. 2017

Cell Chemical Biology

View full text Add to dashboard Cite

Summary Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of Class I HDACs is sufficient to upregulate PGRN in human neurons and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression. Moreover, we identify regions in the GRN promoter in which elevated H3K27 acetylation and transcription factor EB (TFEB) occupancy correlate with HDAC-inhibitor mediated upregulation of PGRN. These findings have implications for epigenetic and cis-regulatory mechanisms controlling human GRN expression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD.

show abstract

Section: Discussionmentioning

confidence: 99%

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

She

Kurtser

Reis

et al. 2017

Cell Chemical Biology

View full text Add to dashboard Cite

show abstract

“…This neuroprotective function is highlighted by the relationship between progranulin and neurodegenerative disease; heterozygous loss‐of‐function mutations in the gene encoding progranulin ( GRN ) cause frontotemporal dementia (FTD),5, 6 and a common rs5848 allele in the 3′UTR of GRN has been associated with both decreased serum and brain progranulin expression levels and increased risk of developing Alzheimer's disease (AD) 7, 8, 9. Additionally, misregulation of progranulin expression has been implicated in parkinsonism, neuronal ceroid lipofuscinosis, and other neuropsychiatric disorders 10, 11…”

Section: Introductionmentioning

confidence: 99%

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Cooper

Nachun

Dokuru

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveChanges in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI).MethodsPeripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF‐MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single‐nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme‐linked immunosorbent assay, and methylation status using methylation microarrays.ResultsWe observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF‐MAC cohort (F 2,505 = 10.41, P = 3.72*10−5). This finding was replicated in the AddNeuroMed (F 2,271 = 17.9, P = 4.83*10−8) but not the ADNI series. The rs5848 SNP (T‐allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories.InterpretationProgranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia.

show abstract

“…PGRN-gene mutations are causative of familial frontotemporal dementia (FTD) [1], a neurodegenerative disorder preferentially affecting the frontal and/or temporal lobes. PGRN has also been related to several other neurodegenerative diseases, such as Alzheimer's disease (AD), multiple sclerosis, and other brain disorders such as bipolar disorder and central nervous system (CNS) HIV-infection [2][3][4][5][6]. PGRN is abundantly expressed throughout the body, and, in the CNS in particular, it is mainly expressed in microglia and neurons where it functions in brain neuroinflammatory processes, neurite outgrowth, and synapse biology [7,8].…”

Section: Introductionmentioning

confidence: 99%

Stability of Progranulin Under Pre-Analytical Conditions in Serum and Cerebrospinal Fluid

Willemse

Durieux-Lu

Flier

et al. 2016

JAD

View full text Add to dashboard Cite

Abstract. Progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF) are increasingly studied as potential markers for neurodegenerative disorders. We aimed to 1) characterize two commercially available PGRN ELISAs on several assay validation parameters, 2) assess the stability of PGRN in serum and CSF under pre-analytical conditions, and 3) compare stability in the two assays. Intra-and inter-assay variation, inter-lot variation, linearity, lower limit of detection, and kit correlations were assessed for the Adipogen and R&D PGRN ELISA kits. Blood and serum samples were experimentally exposed to ≤9 freeze/thaw cycles, delayed processing for ≤24 h at room temperature and 4• C, and to temperature stability tests for ≤3 weeks at -20• C, 4• C, room temperature, and 37 • C. Both commercial PGRN ELISA kits showed acceptable ranges for intra-and inter-assay variation, where the R&D kit performed more accurate than the Adipogen kit, especially for inter-assay variation (intra-assay serum: 6.7 and 8.3%, respectively; inter-assay serum: 9.2 and 21.0%; intra-assay CSF: 3.6 and 12.0%; inter-assay CSF: 16.0 and 44.5%). Absolute serum PGRN concentrations were 1.9-fold higher in Adipogen than R&D (p < 0.001) and strongly correlated between both kits (ρ = 0.86, p < 0.0001) and CSF PGRN levels were on the borderline of detection in both kits. PGRN was typically stable under all pre-analytical conditions addressed, although two weeks at 37• C resulted in decreased PGRN concentrations in CSF, only when using the Adipogen kit. These results support further examination of PGRN as a potential marker in neurodegenerative diseases, since PGRN is stable in serum and CSF and can be measured using ELISA kits from several providers.

show abstract

Further evidence for plasma progranulin as a biomarker in bipolar disorder

Cited by 27 publications

References 25 publications

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Stability of Progranulin Under Pre-Analytical Conditions in Serum and Cerebrospinal Fluid

Contact Info

Product

Resources

About