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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Available from: Philip Van Damme
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    • "Progranulin is involved in multiple biological functions, such as in survival, migration and regulation of cellular proliferation, wound repair and inflammation, and it has also been speculated to play a role in excitotoxicity and synaptic transmission (Guo et al., 2010;Tapia et al., 2011). Specifically, in the CNS, progranulin seems to play a significant role in maintaining physiological functions because it has been observed that it has neuroprotective effects (Van Kampen et al., 2014) and neurotrophic activity in vitro and in vivo model systems (Van Damme et al., 2008;Gao et al., 2010;Laird et al., 2010). Multiple evidence supports that progranulin is involved in different pathological conditions, such as neurodegenerative, psychiatric and metabolic disorders, thus becoming a fascinating target for therapy (Philips et al., 2010;Petkau and Leavitt, 2014;Kanazawa et al., 2015). "
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    ABSTRACT: The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD), which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia, can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF) and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN) genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.
    Full-text · Article · Feb 2016 · Frontiers in Aging Neuroscience
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    • "Experimental research [1] has shown that PRGN levels in the hippocampus following a SE reached their peak at 48 h and persisted at a similar level until 96 h post-SE before decreasing. These elevated PRGN levels might be an indirect sign for neuronal recovery mechanism, because PRGN can function as a growth factor [3]. Cerebrospinal fluid progranulin has been established as a biomarker in some neurodegenerative diseases like Alzheimer's disease or frontotemporal lobe degeneration [12] [13]. "
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    ABSTRACT: Recently, a mouse model showed that progranulin, a mediator in neuroinflammation and a neuronal growth factor, was elevated in the hippocampus after status epilepticus (SE). This elevated level might mirror compensating neuronal mechanisms after SE. Studies concerning neuronal recovery and neuroprotective mechanisms after SE in humans are scarce, so we tested for progranulinin the cerebrospinal fluid (CSF) after various types of SE. We performed a retrospective analysis of progranulin levels in CSF in patients (n=24) who underwent lumbar puncture as part of diagnostic workup after having SE and in patients after having one single tonic-clonic seizure who comprised the control group (n=8). In our group with SE, progranulin levels in CSF were not significantly elevated compared to our control group. Furthermore, there was no correlation between progranulin levels and the time interval between lumbar puncture and SE. Additionally, in cases of higher CSF progranulin levels, we found no impact on the clinical outcome after SE. Although our cohort is heterogeneous and not fully sufficient, we conclude that progranulin in CSF is not elevated after SE in our cohort. Therefore, our results do not suggest a change in cerebral progranulin metabolism as a possible neuroregenerative or neuroprotective mechanism in humans after SE in acute and subacute phases. A larger cohort study is needed to further strengthen this result. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Epilepsy & Behavior
    • "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.
    No preview · Article · Dec 2014 · Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics
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