Progranulin as a Novel Factor in Gaucher Disease

Choy, Francis Y.M.; Christensen, Chloe L.

doi:10.1016/j.ebiom.2016.11.006

Cited by 6 publications

(6 citation statements)

References 9 publications

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“…Moreover, treatment with either PGRN or its small derivative, Pcgin, is able to ameliorate GD phenotype through protein disaggregation in patient fibroblasts and GD model mice[29]. These findings support a role of PGRN as a disease modifying co-factor in GD[29,28,30], and raise the question of whether PGRN’s chaperone functionality is a general mechanism applicable to multiple lysosomal enzymes[31]. Herein, we screened multiple LSDs and identified TSD as additional LSD in which PGRN showed promising therapeutic effects.…”

Section: Introductionmentioning

confidence: 83%

Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease

et al. 2018

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Tay-Sachs disease (TSD) is a lethal lysosomal storage disease (LSD) caused by mutations in the HexA gene, which can lead to deficiency of β-hexosaminidase A (HexA) activity and consequent accumulation of its substrate, GM2 ganglioside. Recent reports that progranulin (PGRN) functions as a chaperone of lysosomal enzymes and its deficiency is associated with LSDs, including Gaucher Disease and neuronal ceroid lipofuscinosis, prompted us to screen the effects of recombinant PGRN on lysosomal storage in fibroblasts from 11 patients affected by various LSDs, which led to the isolation of TSD in which PGRN demonstrated the best effects in reducing lysosomal storage. Subsequent in vivo studies revealed significant GM2 accumulation and the existence of typical TSD cells containing zebra-bodies in both aged and ovalbuminchallenged adult PGRN deficient mice. In addition, HexA, but not HexB, was aggregated in PGRN deficient cells. Furthermore, recombinant PGRN significantly reduced GM2 accumulation and lysosomal storage in these animal models. Mechanistic studies indicated that PGRN bound to HexA through granulin G and E domain, and increased the enzymatic activity and lysosomal delivery of HexA. More importantly, Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively bound to HexA and reduced the GM2 accumulation. Collectively, these studies not only provide new insights into the pathogenesis of TSD, but may also have implications for developing PGRN-based therapy for this lifethreatening disorder.

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Section: Introductionmentioning

confidence: 83%

Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease

et al. 2018

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“…Insufficiency of PGRN also associates with various types of CNS diseases, including frontotemporal lobe dementia (haploinsufficiency) ( Baker et al, 2006 , Cruts et al, 2006 ), Alzheimer disease ( Brouwers et al, 2008 ), and Parkinson disease ( Hu et al, 2006 , Brouwers et al, 2007 ). In addition, intracellular PGRN plays an important role in lysosome biology, and homozygous deficiency of PGRN causes lysosomal storage diseases, including neuronal ceroid lipofuscinosis ( Ahmed et al, 2010 , Smith et al, 2012 ) and Gaucher-like disease ( Jian et al, 2016a , Choy and Christensen, 2016 , Jian et al, 2016b ). Serum levels of PGRN are significantly decreased in GD patients, and GRN variants were found to be prevalent in GD patients.…”

Section: Introductionmentioning

confidence: 99%

Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease

et al. 2018

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We recently reported that progranulin (PGRN) is a novel regulator of glucocerebrosidase and its deficiency associates with Gaucher Diseases (GD) (Jian et al., 2016a; Jian et al., 2018). To isolate the relevant downstream molecules, we performed a whole genome microarray and mass spectrometry analysis, which led to the isolation of Chitinase-3-like-1 (CHI3L1) as one of the up-regulated genes in PGRN null mice. Elevated levels of CHI3L1 were confirmed by immunoblotting and immunohistochemistry. In contrast, treatment with recombinant Pcgin, a derivative of PGRN, as well as imigluerase, significantly reduced the expressions of CHI3L1 in both PGRN null GD model and the fibroblasts from GD patients. Serum levels of CHIT1, a clinical biomarker for GD, were significantly higher in GD patients than healthy controls (51.16 ± 2.824 ng/ml vs 35.07 ± 2.099 ng/ml, p < 0.001). Similar to CHIT1, serum CHI3L1 was also significantly increased in GD patients compared with healthy controls (1736 ± 152.1 pg/ml vs 684.7 ± 68.20 pg/ml, p < 0.001). Whereas the PGRN level is significantly reduced in GD patients as compared to the healthy control (91.56 ± 3.986 ng/ml vs 150.6 ± 4.501, p < 0.001). Collectively, these results indicate that CHI3L1 may be a previously unrecognized biomarker for diagnosing GD and for evaluating the therapeutic effects of new GD drug(s).

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“…During stress, PGRN‐HSP70 prevents the aggregation of lysosomal glucocerebrosidase and lysosomal integral membrane protein 2 (LIMP 2) in the cytoplasm, and facilitates their trafficking to the lysosome. These findings have implications in GD, and PGRN has been reported as a novel disease modifier in GD 4,30 …”

Section: Introductionmentioning

confidence: 80%

“…These findings have implications in GD, and PGRN has been reported as a novel disease modifier in GD. 4,30 Serum PGRN has been found an independent marker of liver fibrosis in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD). 31 However, to our knowledge, the relation between PGRN and liver fibrosis among patients with GD has not been previously explored.…”

Section: Introductionmentioning

confidence: 99%

Serum progranulin levels in paediatric patients with Gaucher disease; relation to disease severity and liver stiffness by transient elastography

Tantawy

Adly

Ismail

et al. 2020

Liver International

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Background Non‐invasive screening for liver fibrosis using transient elastography (TE) could be of value in the management of Gaucher disease (GD). Progranulin (PGRN) is a novel disease modifier in GD and an independent marker of liver fibrosis. Objectives We determined PGRN levels in paediatric patients with GD and assessed its role as a potential marker for disease severity and relation to liver stiffness by TE. Methods Fifty‐one GD patients (20 had type 1 and 31 had type 3) with a median age of 9.5 years were compared to 40 age‐ and sex‐matched healthy controls and were studied focusing on visceral manifestations, neurological disease, haematological profile and PGRN levels as well as abdominal ultrasound and TE. Patients were on enzyme replacement therapy (ERT) for various durations and those with viral hepatitis infection were excluded. Results By TE, 14 GD patients (27.5%) had elevated liver stiffness ≥7.0 kPa. Liver stiffness was significantly higher in type 1 GD patients than type 3 (P = .002), in splenectomized patients (P = .012) and those with dysphagia (P < .001). Liver stiffness was positively correlated with age of onset of ERT (P < .001). PGRN levels were significantly lower in GD patients compared with controls (P < .001). PGRN was significantly lower in GD patients with squint (P = .025), dysphagia (P = .036) and elevated liver stiffness (P = .015). PGRN was positively correlated with white blood cell count (r = .455, P = .002) and haemoglobin (r = .546, P < .001), while negatively correlated with severity score index (r = −.529, P < .001), liver volume (r = −.298, P = .034) and liver stiffness (r = −.652, P < .001). Conclusions Serum PGRN levels were associated with clinical disease severity and elevated liver stiffness in paediatric GD patients.

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Progranulin as a Novel Factor in Gaucher Disease

Cited by 6 publications

References 9 publications

Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease

Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease

Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease

Serum progranulin levels in paediatric patients with Gaucher disease; relation to disease severity and liver stiffness by transient elastography

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