Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival

Laboratory of Neurobiology, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
The Journal of Cell Biology (Impact Factor: 9.83). 05/2008; 181(1):37-41. DOI: 10.1083/jcb.200712039
Source: PubMed


Recently, mutations in the progranulin (PGRN) gene were found to cause familial and apparently sporadic frontotemporal lobe dementia (FTLD). Moreover, missense changes in PGRN were identified in patients with motor neuron degeneration, a condition that is related to FTLD. Most mutations identified in patients with FTLD until now have been null mutations. However, it remains unknown whether PGRN protein levels are reduced in the central nervous system from such patients. The effects of PGRN on neurons also remain to be established. We report that PGRN levels are reduced in the cerebrospinal fluid from FTLD patients carrying a PGRN mutation. We observe that PGRN and GRN E (one of the proteolytic fragments of PGRN) promote neuronal survival and enhance neurite outgrowth in cultured neurons. These results demonstrate that PGRN/GRN is a neurotrophic factor with activities that may be involved in the development of the nervous system and in neurodegeneration.

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    • "The same alterations could also be found in plasma [24]. The reduced CSF proganulin in PGRN mutation carriers but not non-carriers with FTLD or controls was supported by two other studies which showed a similar concentration range of progranulin in CSF but groups of mutation carriers were also small (n = 3) [25] [26]. However, the observed PGRN mutations in these studies are null mutations and reduced CSF or plasma concentrations are in agreement with reduced progranulin expression but do not reflect functional alterations (e.g. "
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) comprises a spectrum of rare neurodegenerative diseases with an estimated prevalence of 15–22 cases per 100,000 persons including the behavioral variant of frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA), semantic dementia (SD), FTD with motor neuron disease (FTD–MND), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The pathogenesis of the diseases is still unclear and clinical diagnosis of FTLD is hampered by overlapping symptoms within the FTLD subtypes and with other neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Intracellular protein aggregates in the brain are a major hallmark of FTLD and implicate alterations in protein metabolism or function in the disease's pathogenesis. Cerebrospinal fluid (CSF) which surrounds the brain can be used to study changes in neurodegenerative diseases and to identify disease-related mechanisms or neurochemical biomarkers for diagnosis. In the present review, we will give an overview of the current literature on proteomic studies in CSF of FTLD patients. Reports of targeted and unbiased proteomic approaches are included and the results are discussed in regard of their informative value about disease pathology and the suitability to be used as diagnostic biomarkers. Finally, we will give some future perspectives on CSF proteomics and a list of candidate biomarkers which might be interesting for validation in further studies. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology.
    Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 12/2014; 1854(7). DOI:10.1016/j.bbapap.2014.12.010 · 2.75 Impact Factor
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    • "Among others, GRN mutations are expected to induce a loss of 50% of progranulin, with a mechanism of haploinsufficiency, and the presence of ubiquitinated TDP-43 protein is the neuropathological hallmark [8], [20], [21]. The physiological role of progranulin, as well as the effect of its reduction in the brain, is still largely unknown, although it has been recently suggested that progranulin might be involved in inflammatory pathways and innate immunity [22], [23], and that it acts as a neurotrophic factor [24]. Improved understanding of the molecular mechanisms of network disintegration will constitute a new paradigm of neurodegenerative disease and monogenic dementias. "
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    ABSTRACT: BackgroundMonogenic dementias represent a great opportunity to trace disease progression from preclinical to symptomatic stages. Frontotemporal Dementia related to Granulin (GRN) mutations presents a specific framework of brain damage, involving fronto-temporal regions and long inter-hemispheric white matter bundles. Multimodal resting-state functional MRI (rs-fMRI) is a promising tool to carefully describe disease signature from the earliest disease phase.ObjectiveTo define local connectivity alterations in GRN related pathology moving from the presymptomatic (asymptomatic GRN mutation carriers) to the clinical phase of the disease (GRN- related Frontotemporal Dementia).MethodsThirty-one GRN Thr272fs mutation carriers (14 patients with Frontotemporal Dementia and 17 asymptomatic carriers) and 38 healthy controls were recruited. Local connectivity measures (Regional Homogeneity (ReHo), Fractional Amplitude of Low Frequency Fluctuation (fALFF) and Degree Centrality (DC)) were computed, considering age and gender as nuisance variables as well as the influence of voxel-level gray matter atrophy.ResultsAsymptomatic GRN carriers had selective reduced ReHo in the left parietal region and increased ReHo in frontal regions compared to healthy controls. Considering Frontotemporal Dementia patients, all measures (ReHo, fALFF and DC) were reduced in inferior parietal, frontal lobes and posterior cingulate cortex. Considering GRN mutation carriers, an inverse correlation with age in the posterior cingulate cortex, inferior parietal lobule and orbitofrontal cortex was found.ConclusionsGRN pathology is characterized by functional brain network alterations even decades before the clinical onset; they involve the parietal region primarily and then spread to the anterior regions of the brain, supporting the concept of molecular nexopathies.
    PLoS ONE 09/2014; 9(9):e106500. DOI:10.1371/journal.pone.0106500 · 3.23 Impact Factor
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    • "Progranulin (PGRN) is involved in several physiological and pathophysiological processes, in the periphery as well as in the central nervous system. There is evidence that progranulin functions as a neurotrophic factor and modulates neurite outgrowth, neuronal differentiation and neuronal survival (Van Damme et al., 2008; Gao et al., 2010). Therefore it is not surprising that increased progranulin expression can be found in neuroinflammatory and neurodegenerative processes, like Alzheimer's disease, Creutzfeld–Jakob disease and amyotrophic lateral sclerosis (Ahmed et al., 2007). "
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    ABSTRACT: Background A recent study suggested that progranulin (encoded by the fronto-temporal dementia risk gene GRN) plasma levels are decreased in bipolar disorder (BD). Replication of this finding is however lacking. Methods Progranulin plasma levels of bipolar patients (n=104) and healthy controls (n=80) were measured by enzyme-linked immunosorbent assay (ELISA). Participants were also genotyped for three single nucleotide polymorphisms (SNPs) in the GRN gene (rs2879096, rs4792938 and rs5848), and the effect of genetic variation on progranulin levels was examined. Results Plasma progranulin levels were decreased in BD (ANCOVA, p=0.001). Furthermore, age was significantly and positively correlated with plasma progranulin (Pearson׳s correlation, r=0.269, p<0.001). Also, lithium treatment but no other medication had a significant effect on progranulin plasma levels (ANCOVA, p=0.007). Specifically in BD, the GRN SNP rs5848 was associated with progranulin plasma levels (Kruskal–Wallis test, p<0.005). Limitations Subgroup analysis regarding bipolar I vs. bipolar II subtype and polarity of the episode at sampling (manic vs. depressed vs. mixed vs. rapid cycling vs. euthymic) could only be performed with limited validity due to the relatively small sample size. The suitability of peripheral progranulin as a biomarker for BD is limited due to the overlap between patients and controls. Conclusion The findings strengthen the evidence for progranulin being involved in pathomechanisms of bipolar disorder, and suggest a genetic determinant of progranulin concentrations that is relevant specifically in bipolar patients.
    Journal of Affective Disorders 03/2014; 157:87–91. DOI:10.1016/j.jad.2014.01.006 · 3.38 Impact Factor
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