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

ABSTRACT 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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Available from: Philip Van Damme, Sep 28, 2015
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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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    • "It may be hypothesized that the sciatic nerve injury on one side and the subsequent restructuring of sensory and motor neuronal networks might be particularly unfavorable for tasks requiring discrimination of right and left. Progranulin deficient mice likely lose more neurons after axonal injury because lack of this neurotrophic factor reduces the ability of the neurons to survive the neuronal stress (Van Damme et al., 2008; Gao et al., 2010; Gass et al., 2012; Lim et al., 2012). The importance of progranulin may increase with age. "
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    ABSTRACT: Persistent neuropathic pain is a frequent consequence of peripheral nerve injuries, particularly in the elderly. Using the IntelliCage we studied if sciatic nerve injury obstructed learning and memory in young and aged mice, each in wild type and progranulin deficient mice, which develop premature signs of brain aging. Both young and aged mice developed long-term nerve injury-evoked hyperalgesia and allodynia. In both genotypes, aged mice with neuropathic pain showed high error rates in place avoidance acquisition tasks. However, once learnt, these aged mice with neuropathic pain showed a significantly stronger maintenance of the aversive memory. Nerve injury did not affect place preference behavior in neither genotype, neither in young nor aged mice. However, nerve injury in progranulin deficient mice impaired the learning of spatial sequences of awarded places, particularly in the aged mice. This task required a discrimination of clockwise and anti-clockwise sequences. The chaining failure occurred only in progranulin deficient mice after nerve injury, but not in sham operated or wildtype mice, suggesting that progranulin was particularly important for compensatory adaptations after nerve injury. In contrast, all aged mice with neuropathic pain, irrespective of the genotype, had a long maintenance of aversive memory suggesting a negative alliance and possibly mutual aggravation of chronic neuropathic pain and aversive memory at old age.
    Frontiers in Behavioral Neuroscience 11/2013; 7:174. DOI:10.3389/fnbeh.2013.00174 · 3.27 Impact Factor
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