Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis

Vercellino, Marco; Grifoni, Silvia; Romagnolo, Alberto; Masera, Silvia; Mattioda, Alessandra; Trebini, Claudia; Chiavazza, Carlotta; Caligiana, Laura; Capello, Elisabetta; Mancardi, Gianluigi; Giobbe, Dario; Mutani, Roberto; Giordana, Maria Teresa; Cavalla, Paola

doi:10.1177/1352458511406164

Cited by 54 publications

(44 citation statements)

References 24 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with its immunomodulatory role, progranulin expression was found to be induced in multiple sclerosis, a classic example of neuroinflammation (65). How- ever, no difference in cerebrospinal fluid progranulin levels was reported in multiple sclerosis in an earlier study (66).…”

Section: What Does Progranulin Do?mentioning

confidence: 89%

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

203

196

View full text Add to dashboard Cite

GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. Progranulin: The BasicsProgranulin (encoded by GRN) is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1-5). In the brain, intracellular expression is highest in neurons and activated microglia (6 -8). At the subcellular level, progranulin colocalizes with the endoplasmic reticulum and Golgi markers in the secretory pathway and the lysosomal marker Lamp1 (9, 10). Progranulin is a secreted glycoprotein and is readily detected in blood and cerebrospinal fluid (11)(12)(13).Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14), but seemingly not in Drosophila. It has no robust sequence homology to any other known protein family. Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases (see Fig. 1). These "granulins" were discovered first, before the cloning of the full-length gene. Whether the biological activities of progranulin are mediated by the full-length protein, individual granulins, or both is not clear. We begin our discussion with the consequences of progranulin deficiency. Progranulin Haploinsufficiency Causes Frontotemporal Lobar Degeneration with Ubiquitinated TDP-43-positive InclusionsIn 2006, mutations in GRN were discovered to be a cause of frontotemporal lobar degeneration (FTLD) 3 with ubiquitinated TDP-43-positive inclusions (FTLD-TDP) (15,16). FTLD is the second most common presenile dementia disorder after Alzheimer disease, representing 5-15% of all dementias (17,18). More than 70 mutations in GRN, almost all of which result in null alleles, have been identified in FTLD patients. A few causative missense mutations also result in reduced levels of progranulin (19).Clinical manifestations of heterozygous loss-of-function GRN mutations include variants of the FTLD spectrum, parkinsonism, and the corticobasal syndrome (20). Neuropathologically, atrophy of the brain parenchyma (most severe in the frontal cortex) is usually observed. The atrophy can be asymmetrical, and different brain regions are affected with varying frequency. Loss of pigmentation of the substantia nigra, hippocam...

show abstract

Section: What Does Progranulin Do?mentioning

confidence: 89%

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

203

196

View full text Add to dashboard Cite

show abstract

“…PGRN exhibits neurotrophic and anti-inflammatory activities, whereas GRNs serve as a proinflammatory mediator. Expression levels of PGRN, whose release is facilitated by anti-inflammatory stimuli in microglia, are elevated in multiple sclerosis brains [28,29]. Astrocytes produce large amounts of secretory leukocyte protease inhibitor, a negative regulator of proteolytic processing of PGRN, in response to proinflammatory stimuli [28].…”

Section: Discussionmentioning

confidence: 99%

TMEM106B expression is reduced in Alzheimer’s disease brains

Satoh

Kino

Kawana

et al. 2014

Alzheimers Res Ther

View full text Add to dashboard Cite

IntroductionTMEM106B is a transmembrane glycoprotein of unknown function located within endosome/lysosome compartments expressed ubiquitously in various cell types. Previously, the genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), particularly in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations. Recent studies indicate that TMEM106B plays a pathological role in various neurodegenerative diseases, including Alzheimer’s disease (AD). However, at present, the precise levels of TMEM106B expression in AD brains remain unknown.MethodsBy quantitative reverse transcription (RT)-PCR (qPCR), western blot and immunohistochemistry, we studied TMEM106B and PGRN expression levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson’s disease, multiple system atrophy and non-neurological cases.ResultsIn AD brains, TMEM106B mRNA and protein levels were significantly reduced, whereas PGRN mRNA levels were elevated, compared with the levels in non-AD brains. In all brains, TMEM106B was expressed in the majority of cortical neurons, hippocampal neurons, and some populations of oligodendrocytes, reactive astrocytes and microglia with the location in the cytoplasm. In AD brains, surviving neurons expressed intense TMEM106B immunoreactivity, while senile plaques, neurofibrillary tangles and the perivascular neuropil, almost devoid of TMEM106B, intensely expressed PGRN.ConclusionsWe found an inverse relationship between TMEM106B (downregulation) and PGRN (upregulation) expression levels in AD brains, suggesting a key role of TMEM106B in the pathological processes of AD.

show abstract

“…In humans, the elevation of PGRN is observed in local inflammatory tissues, such as in brains in patients with active multiple sclerosis [27] and in the synovium of rheumatoid arthritis (RA) patients [28]. We measured concentrations of serum PGRN in patients with RA ( n = 33).…”

Section: Discussionmentioning

confidence: 99%

Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity

et al. 2012

View full text Add to dashboard Cite

IntroductionProgranulin (PGRN) is the precursor of granulin (GRN), a soluble cofactor for toll-like receptor 9 (TLR9) signaling evoked by oligonucleotide (CpG)-DNA. Because TLR9 signaling plays an important role in systemic lupus erythematosus (SLE), we investigated whether PGRN is involved in the pathogenesis of SLE.MethodsWe measured concentrations of serum PGRN and interleukin-6 (IL-6) with enzyme-linked immunosorbent assay (ELISA) in patients with SLE (n = 68) and in healthy controls (n = 60). We assessed the correlation between the serum PGRN levels and established disease-activity indexes. The sera from the patients with high PGRN titers (>80 ng/ml) at the initial evaluation were reevaluated after the disease was ameliorated by treatment. We also measured the IL-6 concentration secreted by peripheral blood mononuclear cells (PBMCs) incubated with (a) oligonucleotide (CpG-B) in the presence or absence of recombinant human PGRN (rhPGRN); and (b) lupus sera in the presence or absence of a neutralizing anti-PGRN antibody.ResultsSerum PGRN levels were significantly higher in SLE patients than healthy controls. Their levels were significantly associated with activity of clinical symptoms. They also significantly correlated with values of clinical parameters, including the SLE Disease Activity Index and anti-double-stranded DNA antibody titers, and inversely with CH50, C3, and C4 levels. Moreover, serum PGRN levels significantly decreased after successful treatment of SLE. The rhPGRN significantly upregulated the production of IL-6 by PBMCs stimulated with CpG-B. Patients' sera stimulated production of IL-6 from PBMCs, which was significantly impaired by neutralization of PGRN. The serum PGRN levels significantly correlated with the serum IL-6 levels.ConclusionsSerum PGRN could be a useful biomarker for disease activity of SLE. PGRN may be involved in the pathogenesis of SLE partly by enhancing the TLR9 signaling.

show abstract

Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis

Abstract: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.

Cited by 54 publications

References 24 publications

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

TMEM106B expression is reduced in Alzheimer’s disease brains

Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity

Contact Info

Product

Resources

About