Sensitivity to neurotoxic stress is not increased in progranulin-deficient mice

Loss-of-function mutations in the progranulin (GRN) gene are a common cause of autosomal dominant frontotemporal lobar degeneration, a fatal and progressive neurodegenerative disorder common in people less than 65 years of age. In the brain, progranulin is expressed in multiple regions at varying levels, and has been hypothesized to play a neuroprotective or neurotrophic role. Four neurotoxic agents were injected in vivo into constitutive progranulin knockout (Grn^−/−) mice and their wild-type (Grn^+/+) counterparts to assess neuronal sensitivity to toxic stress. Administration of 3-nitropropionic acid, quinolinic acid, kainic acid, and pilocarpine induced robust and measurable neuronal cell death in affected brain regions, but no differential cell death was observed between Grn^+/+ and Grn^−/− mice. Thus, constitutive progranulin knockout mice do not have increased sensitivity to neuronal cell death induced by the acute chemical models of neuronal injury used in this study.     

The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding

Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E–SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.     

The genetics of primary progressive aphasia

Background: Primary progressive aphasia (PPA) is a disorder in which language impairment is the initial and predominant symptom. Three main phenotypes are described, the nonfluent variant (nfvPPA), the semantic variant (svPPA) and the logopenic variant (lvPPA). Although PPA is most commonly a sporadic disorder, recent studies have shown an association of PPA with mutations in a number of genes.

Aims: To understand the extent to which PPA may be inherited, which genetic mutations may cause it, and whether the phenotypes of genetic PPA differ from sporadic PPA.

Main Contribution: In around 20–30% of patients with PPA, a family history is present although nfvPPA is more heritable than svPPA and lvPPA which are both usually sporadic disorders. Mutations in the progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), genes are the major causes of genetic PPA.

Conclusions: Key pointers that may suggest testing for a GRN mutation in PPA are a family history of one of the disorders within the frontotemporal dementia spectrum, a nfvPPA phenotype, particularly if presenting with a prominent anomia and asymmetrical fronto-temporo-parietal atrophy. In someone with nfvPPA and a family history, GRN should be tested initially but a search for hexanucleotide repeat expansions in the C9orf72 gene should be performed if negative, particularly if there are features of motor neurone disease, or a family history of someone with motor neurone disease. Mutations in other genes are only very rare causes of PPA but if GRN and C9orf72 are both negative, testing for mutations in the microtubule-associated protein tau (MAPT), valosin-containing protein (VCP) and presenilin 1 (PSEN1) should be considered.     

Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA‐binding protein 43 inclusions) in missense progranulin mutation Cys139Arg

Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau‐negative frontotemporal lobar degeneration with TAR DNA‐binding protein 43‐positive inclusions (FTLD‐TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late‐onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ‐amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD‐TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD‐TDP.     

No major progranulin genetic variability contribution to disease etiopathogenesis in an ALS Italian cohort

To analyze the contribution of progranulin (PGRN) to the etiopathogenesis of amyotrophic lateral sclerosis (ALS), we performed a PGRN gene screening in 146 Italian patients (12 familial cases) and evaluated the association of two common variants with risk of developing ALS in 239 sporadic cases (SALS). Progranulin mRNA and protein levels were measured in peripheral blood mononuclear cells and serum of a subset of these patients and controls. PGRN sequence analysis revealed a heterozygous change (p.S120Y), previously observed in an independent sporadic ALS-FTD patient. Haplotype analysis showed a conserved PGRN region among these two subjects consistent with possible common ancestor allele. Two non-coding polymorphisms were not associated to increased risk to develop ALS; mRNA and serum levels were not significantly different between cases and controls. Overall, our data argue against the hypothesis of progranulin as a major risk factor for motor neuron dysfunction, at least in Italian population. The p.S120Y variant may characterize rare patients with SALS, although its pathogenetic mechanism remains to be elucidated.     

The complex aetiology of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is now a widely recognised form of dementia. This heterogeneous disease has been of particular interest to geneticists due to its high rate of heritability with up to 40% of patients reporting a family history of the disease in at least one extra family member. There have been several chromosome loci linked to this disorder and three genes have already been identified. Remarkably, it has been recently demonstrated that 2 of these are only 1.7 Mb from one another on chromosome 17q21, these being tau and progranulin. The identification of these genes has contributed greatly to our understanding of the differing neuropathologies associated with FTLD. Furthermore, the discovery that TDP-43 is a component of the neuronal inclusions seen in the most common neuropathological subtype has also helped expand the biochemical pathways that are the focus of much FTLD research. Nevertheless, other genes causing FTLD remain to be identified and their biology elucidated before we have a complete understanding of the complex aetiology of this disease.     

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

Granulin (GRN) mutations have been identified as a major cause of frontotemporal lobar degeneration (FTLD) by haploinsufficiency mechanism, although their effects on brain tissue dysfunction and damage still remain to be clarified. In this study, we investigated the pattern of neuroimaging abnormalities in FTLD patients, carriers and noncarriers of GRN Thr272fs mutation, and in presymptomatic carriers. We assessed regional gray matter (GM) atrophy, and resting (RS)-functional magnetic resonance imaging (fMRI). The functional connectivity maps of the salience (SN) and the default mode (DMN) networks were considered. Frontotemporal gray matter atrophy was found in all FTLD patients (more remarkably in those GRN Thr272fs carriers), but not in presymptomatic carriers. Functional connectivity within the SN was reduced in all FTLD patients (again more remarkably in those mutation carriers), while it was enhanced in the DMN. Conversely, presymptomatic carriers showed increased connectivity in the SN, with no changes in the DMN. Our findings suggest that compensatory mechanisms of brain plasticity are present in GRN-related FTLD, but with different patterns at a preclinical and symptomatic disease stage.     

The association between dietary antioxidants and adipokines level among obese women

AimAdipokines are associated with several oxidative stress-related diseases and pathologic conditions. We aimed to assess the association between antioxidants and adipokines in obese adults.Methods and MaterialsIn this cross-sectional study, a total of 160 obese women were included. Body composition and anthropometric characteristics were measured. Dietary intakes were assessed by 3-day, 24-h dietary recall. Blood samples were obtained following an overnight fasting. Serum concentrations of adipokines including progranulin, retinol binding protein 4 (RBP4) and Angiopoietin-related growth factor 6 (ANGPTL6) was measured using an enzyme-linked immunosorbent assay. ANCOVA and the linear regression model analysis was performed to assess the relationship between Progranulin, RBP4, AnGPTL6, and antioxidants.ResultsMean age of included women was 39.31 ± 12.10. Mean and standard deviation for BMI was 35.05 ± 4.26 in this obese population. There was a positive significant association between ANGPTL6 and vitamin D intake (p < 0.001). Also, there was a marginal association between RBP4 and vitamin A (p = 0.063) intake, but after adjustment age, and fat mass, we found a significant association (p = 0.008). However, the associations between dietary antioxidants, progranulin, and ANGPTL6 were not statistically significant.ConclusionsANGPTL6 and RBP4 levels directly associated with dietary vitamins D and A intake, respectively. But, according to the results, the association between ANGPTL6 and vitamin D was bidirectional. The suggested associations probably can be useful in the development of interventional studies for management of chronic diseases.     

A novel role for drebrin in regulating progranulin bioactivity in bladder cancer

We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer.