Cellular ageing, increased mortality and FTLD‐TDP‐associated neuropathology in progranulin knockout mice

Wils, Hans; Kleinberger, Gernot; Pereson, Sandra; Janssens, Jonathan; Capell, Anja; Dam, Debby Van; Cuijt, Ivy; Joris, Geert; Deyn, Peter Paul De; Haass, Christian; Broeckhoven, Christine Van; Kumar‐Singh, Samir

doi:10.1002/path.4043

Cited by 119 publications

(135 citation statements)

References 42 publications

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“…PGRN deficiency resulted in neuronal loss, increased gliosis, lipofuscin accumulation in the VPM/VPL, and defective myelination in the cerebral cortex. These pathological changes in aged PGRN-deficient mice are partially consistent with previous studies [11,13,33], though the brain regions examined were different. Analyses using NCL model mice in the previous studies revealed that glial activation precedes neuronal loss in the VPM/VPL [17,34].…”

Section: Discussionsupporting

confidence: 91%

“…Disruption of both the ubiquitin-proteasome system and the autophagy-lysosomal system is one of the characteristic features of FTLD with TDP-43 inclusions in the cytoplasm of neurons [27], and impaired production of PGRN is involved in this pathology [5][6][7]. Previous studies reported increased TDP-43 phosphorylation in PGRN-deficient mice [11,13,28]. In the present study, TDP-43 colocalized with p62 in the cytoplasm of neurons as well as the phosphorylated TDP-43 aggregate in the VPM/VPL were only observed in aged PGRN-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

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Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

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Introduction: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10-and 90-week-old wild-type and PGRN-deficient mice. Results: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

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“…Ahmed et al (7) recently showed that intracytoplasmic ubiquitinated aggregates observed in these mice are probably composed of lipofuscin. This finding was replicated in an independent Grn Ϫ/Ϫ line (36). Although some vacuolation was observed in the habenula and hippocampus in very old (23 months) Grn Ϫ/Ϫ mice (7), overt neuronal loss seems to be very mild or absent (34), in contrast with the severe atrophy observed in human FTLD.…”

Section: Mouse Models Of Progranulin Deficiencymentioning

confidence: 74%

“…Behaviorally, the most consistent finding is social interaction deficits (33)(34)(35). In a classic test of hippocampal learning and memory (Morris water maze), Grn Ϫ/Ϫ mice had mild deficits at old age (18 -21 months) in two studies (33,36) but no deficits at 8 months of age in another study (35). Other reported behavioral deficits include depression-like behavior and either increased (35,37) or decreased (33) anxiety.…”

Section: Mouse Models Of Progranulin Deficiencymentioning

confidence: 92%

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

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

207

196

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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...

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“…Recent studies revealed an abnormal accumulation of lipofuscin granules in mice brain regions with ablation of progranulin, accompanied by significantly increased p62 (Bjørkøy et al 2005, Wils et al 2012, suggesting impairment of the autophagylysosomal system in mice brains with ablation of progranulin. Furthermore, autophagy has been closely linked to inflammation in part by regulation of adipokine production.…”

Section: Introductionmentioning

confidence: 99%

Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice

Zhou¹,

Li²,

Liu³

et al. 2015

Journal of Molecular Endocrinology

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Progranulin (PGRN) has recently emerged as an important regulator for insulin resistance. However, the direct effect of PGRN in vivo and the underlying role of progranulin in adipose insulin resistance involving the autophagy mechanism is not fully understood. In this study, mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin sensitivity, remarkable adipose autophagy as well as attenuated insulin signaling via inhibition of mammalian target of rapamycin (mTOR) pathway. Furthermore, blockade of tumor necrosis factor receptor 1 (TNFR1) by TNFR1BP-Fc injection resulted in the restoration of impaired insulin sensitivity and insulin signaling induced by PGRN. Consistent with these findings in vivo, PGRN treatment induced defective insulin signaling, abnormal autophagic and mitochondrial activity in cultured adipocytes, while such effects were nullified by the blockade of TNFR1. In addition, PGRN-deficient adipocytes were more refractory to tunicamycin-or dexamethasone-induced insulin resistance, indicating the causative role of the TNFR1 pathway in the action of PGRN. Collectively, our findings support the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing autophagy via the TNFR1-dependent mechanism.

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Cellular ageing, increased mortality and FTLD‐TDP‐associated neuropathology in progranulin knockout mice

Cited by 119 publications

References 42 publications

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

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

Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice

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