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Progranulin

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https://www.readbyqxmd.com/read/29044416/disease-and-region-specificity-of-granulin-immunopositivities-in-alzheimer-disease-and-frontotemporal-lobar-degeneration
#1
Qinwen Mao, Dongyang Wang, Yanqing Li, Missia Kohler, Jayson Wilson, Zachary Parton, Bella Shmaltsuyeva, Demirkan Gursel, Rosa Rademakers, Sandra Weintraub, Marek-Marsel Mesulam, Haibin Xia, Eileen H Bigio
Heterozygous loss-of-function mutations in GRN, the progranulin gene, which result in progranulin (PGRN) protein haploinsufficiency, are a major cause of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). PGRN is composed of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. To better understand the role of PGRN and granulin (Grn) peptides in the pathogenesis of neurodegeneration, we evaluated PGRN/Grn in brains of patients with Alzheimer disease, FTLD-TDP type A with or without GRN mutations, and normal individuals, using a panel of monoclonal antibodies against Grn peptides A-G...
November 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29039535/clinical-implications-of-progranulin-in-gastric-cancer-and-its-regulation-via-a-positive-feedback-loop-involving-akt-and-erk-signaling-pathways
#2
Dong Yang, Ruidong Li, Huili Wang, Junye Wang, Lei Han, Lihua Pan, Xueqin Li, Qingli Kong, Guijuan Wang, Xiujun Su
In previous years, progranulin (PGRN) has attracted increasing attention due to its oncogenic roles in several types of tumor. However, the clinical relevance of PGRN in gastric cancer remains to be elucidated. In the present study, 120 retrospective tissue samples were obtained from patients with primary gastric cancer, and the expression of PGRN was detected using immunohistochemistry. The results showed that 71 cases exhibited a high expression of PGRN, which was markedly higher than the 49 cases with a low expression of PGRN...
October 17, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29036611/progranulin-mediated-deficiency-of-cathepsin-d-results-in-ftd-and-ncl-like-phenotypes-in-neurons-derived-from-ftd-patients
#3
Clarissa Valdez, Yvette C Wong, Michael Schwake, Guojun Bu, Zbigniew K Wszolek, Dimitri Krainc
Frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders characterized by cognitive and behavioral impairments. Heterozygous mutations in progranulin (PGRN) cause familial FTD and result in decreased PGRN expression, while homozygous mutations result in complete loss of PGRN expression and lead to the neurodegenerative lysosomal storage disorder neuronal ceroid lipofuscinosis (NCL). However, how dose-dependent PGRN mutations contribute to these two different diseases is not well understood...
September 25, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29031143/c5a-c5ar-pathway-accelerates-renal-ischemia-reperfusion-injury-by-downregulating-pgrn-expression
#4
Kun Zhang, Gui-Qing Li, Qian-Hui He, You Li, Ming Tang, Quan-You Zheng, Gui-Lian Xu, Ke-Qin Zhang
Recent reports indicate that the complement C5a/C5aR pathway and progranulin (PGRN) deficiency both contribute to ischemia-reperfusion (IR)-induced acute kidney injury. However, the underlying relationship between the C5a/C5aR signaling pathway and PGRN expression during acute kidney injury is poorly understood. In this study, we showed that C5aR expression was significantly upregulated after renal IR, and that C5aR deficiency led to a marked increase in PGRN expression and a significant reduction in tubular damage and production of inflammatory cytokines...
October 11, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28982738/intranasal-administration-of-recombinant-progranulin-inhibits-bronchial-smooth-muscle-hyperresponsiveness-in-mouse-allergic-asthma
#5
Yoshihiko Chiba, Shunta Danno, Rena Suto, Wataru Suto, Yamato Yamane, Motohiko Hanazaki, Hiroshi Katayama, Hiroyasu Sakai
Progranulin (PGRN) is a growth factor with multiple biological functions, and has been suggested as an endogenous inhibitor of TNFα-mediated signaling. TNFα is believed as one of the important mediators of the pathogenesis of asthma, including airway hyperresponsiveness (AHR). In the present study, effects of recombinant PGRN on the TNFα-mediated signaling and the antigen-induced hyper-contractility were examined in bronchial smooth muscles (BSMs) both in vitro and in vivo. Cultured human BSM cells (hBSMCs) and male BALB/c mice were used...
October 5, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28944282/progranulin-acts-as-a-shared-chaperone-and-regulates-multiple-lysosomal-enzymes
#6
Jinlong Jian, Aubryanna Hettinghouse, Chuan-Ju Liu
Multifunctional factor progranulin (PGRN) plays an important role in lysosomes, and its mutations and insufficiency are associated with lysosomal storage diseases, including neuronal ceroid lipofuscinosis and Gaucher disease (GD). The first breakthrough in understanding the molecular mechanisms of PGRN as regulator of lysosomal storage diseases came unexpectedly while investigating the role of PGRN in inflammation. Challenged PGRN null mice displayed typical features of GD. In addition, GRN gene variants were identified in GD patients and the serum levels of PGRN were significantly lower in GD patients...
September 2017: Genes & Diseases
https://www.readbyqxmd.com/read/28916533/sex-differences-in-the-prevalence-of-genetic-mutations-in-ftd-and-als-a-meta-analysis
#7
REVIEW
Ashley F Curtis, Mario Masellis, Ging-Yuek Robin Hsiung, Rahim Moineddin, Kathy Zhang, Bonnie Au, Geneva Millett, Ian Mackenzie, Ekaterina Rogaeva, Mary C Tierney
OBJECTIVE: To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)-in patients clinically diagnosed with these conditions. METHODS: MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016)...
October 10, 2017: Neurology
https://www.readbyqxmd.com/read/28915852/a-novel-frameshift-grn-mutation-results-in-frontotemporal-lobar-degeneration-with-a-distinct-clinical-phenotype-in-two-siblings-case-report-and-literature-review
#8
Takashi Hosaka, Kazuhiro Ishii, Takeshi Miura, Naomi Mezaki, Kensaku Kasuga, Takeshi Ikeuchi, Akira Tamaoka
BACKGROUND: Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity...
September 15, 2017: BMC Neurology
https://www.readbyqxmd.com/read/28903038/lipidomic-and-transcriptomic-basis-of-lysosomal-dysfunction-in-progranulin-deficiency
#9
Bret M Evers, Carlos Rodriguez-Navas, Rachel J Tesla, Janine Prange-Kiel, Catherine R Wasser, Kyoung Shin Yoo, Jeffrey McDonald, Basar Cenik, Thomas A Ravenscroft, Florian Plattner, Rosa Rademakers, Gang Yu, Charles L White, Joachim Herz
Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distinguish them from normal and other pathologic groups...
September 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/28899992/depletion-of-progranulin-reduces-glun2b-containing-nmda-receptor-density-tau-phosphorylation-and-dendritic-arborization-in-mouse-primary-cortical-neurons
#10
Francesca Longhena, Michela Zaltieri, Jessica Grigoletto, Gaia Faustini, Luca La Via, Roberta Ghidoni, Luisa Benussi, Cristina Missale, PierFranco Spano, Arianna Bellucci
Loss-of-function mutations in the progranulin (PGRN) gene are a common cause of familial frontotemporal lobar degeneration (FTLD). This age-related neurodegenerative disorder, characterized by brain atrophy in the frontal and temporal lobes and such typical symptoms as cognitive and memory impairment, profound behavioral abnormalities, and personality changes is thought to be related to connectome dysfunctions. Recently, PGRN reduction has been found to induce a behavioral phenotype reminiscent of FTLD symptoms in mice by affecting neuron spine density and morphology, suggesting that the protein can influence neuronal structural plasticity...
November 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28890134/modifiers-of-grn-associated-frontotemporal-lobar-degeneration
#11
REVIEW
Eline Wauters, Sara Van Mossevelde, Julie Van der Zee, Marc Cruts, Christine Van Broeckhoven
Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials...
October 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28884306/probiotic-soy-milk-consumption-and-renal-function-among-type-2-diabetic-patients-with-nephropathy-a-randomized-controlled-clinical-trial
#12
Maryam Miraghajani, Nafiseh Zaghian, Abolfazl Dehkohneh, Maryam Mirlohi, Reza Ghiasvand
Diabetic nephropathy (DN) is one the most important complications of diabetes leading to end-stage renal disease. Dietary approaches have been considered to control of the kidney function deterioration among these patients. The aim of the present study was to determine the effects of fortified soy milk with Lactobacillus plantarum A7 on renal function biomarkers in type 2 DN patients. Forty-eight DN subjects were attended to this parallel randomized trial study. Participants were randomly assigned to consume a diet containing 200 mL/day probiotic soy milk in intervention group or soy milk in the control condition for 8 weeks...
September 8, 2017: Probiotics and Antimicrobial Proteins
https://www.readbyqxmd.com/read/28869469/trehalose-improves-cognition-in-the-transgenic-tg2576-mouse-model-of-alzheimer-s-disease
#13
Stuart D Portbury, Dominic J Hare, Charlotte Sgambelloni, Kali Perronnes, Ashley J Portbury, David I Finkelstein, Paul A Adlard
This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer's disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition metals, iron, copper, and zinc, are understood to be intricately involved in the cellular cascades leading to the defining pathologies of the disease, we sought to determine any parallel impact of trehalose treatment on metal levels...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28865024/homer-spikar-and-other-drebrin-binding-proteins-in-the-brain
#14
Hiroyuki Yamazaki, Tomoaki Shirao
Drebrin is a major F-actin-binding protein in the brain. In the past two decades, many drebrin-binding proteins in addition to F-actin have been identified in several research fields including neuroscience, oncology, and immunology. Among the drebrin-binding proteins, there are various kinds of proteins including scaffold proteins, nuclear proteins, phosphatases, microtubule-binding proteins, G-actin-binding proteins, gap junction proteins, chemokine receptors, and cell-adhesion-related proteins. The interaction between drebrin and its binding partners seems to play important roles in higher brain functions, because drebrin is involved in the pathogenesis of some neurological diseases with cognitive defects...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28859337/amygdala-tdp-43-pathology-in-frontotemporal-lobar-degeneration-and-motor-neuron-disease
#15
Takahiro Takeda, Danielle Seilhean, Isabelle Le Ber, Stéphanie Millecamps, Véronique Sazdovitch, Kazuo Kitagawa, Toshiki Uchihara, Charles Duyckaerts
TDP-43-positive inclusions are present in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) including amyotrophic lateral sclerosis. Behavioral abnormalities, one of the chief symptoms of FTLD, could be, at least partly, related to amygdala pathology. We examined TDP-43 inclusions in the amygdala of patients with sporadic FTLD/MND (sFTLD/MND), FTLD/MND with mutation of the C9ORF72 (FTLD/MND-C9) and FTLD with mutation of the progranulin (FTLD-GRN). TDP-43 inclusions were common in each one of these subtypes, which can otherwise be distinguished on topographical and genetic grounds...
September 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28845019/progranulin-haploinsufficiency-reduces-amyloid-beta-deposition-in-alzheimer-s-disease-model-mice
#16
Masato Hosokawa, Yoshinori Tanaka, Tetsuaki Arai, Hiromi Kondo, Haruhiko Akiyama, Masato Hasegawa
Granulin (Grn) mutations were identified in familial frontotemporal lobar degeneration (FTLD) patients with TDP-43 pathology. Grn transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in FTLD pathogenesis. Moreover, recent findings indicate that Grn mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer's disease. To investigate the influence of PGRN on amyloid beta (Aβ) accumulation, amyloid precursor protein (APP) transgenic mice were interbred with Grn-deficient mice, producing APP transgenic mice harboring the Grn hemizygote (APP/Grn(+/-))...
August 25, 2017: Experimental Animals
https://www.readbyqxmd.com/read/28837568/progranulin-gene-delivery-reduces-plaque-burden-and-synaptic-atrophy-in-a-mouse-model-of-alzheimer-s-disease
#17
Jackalina M Van Kampen, Denis G Kay
Progranulin (PGRN) is a multifunctional protein that is widely expressed throughout the brain, where it has been shown to act as a critical regulator of CNS inflammation and also functions as an autocrine neuronal growth factor, important for long-term neuronal survival. PGRN has been shown to activate cell signaling pathways regulating excitoxicity, oxidative stress, and synaptogenesis, as well as amyloidogenesis. Together, these critical roles in the CNS suggest that PGRN has the potential to be an important therapeutic target for the treatment of various neurodegenerative disorders, particularly Alzheimer's disease (AD)...
2017: PloS One
https://www.readbyqxmd.com/read/28835281/lysosomal-processing-of-progranulin
#18
Xiaolai Zhou, Daniel H Paushter, Tuancheng Feng, Lirong Sun, Thomas Reinheckel, Fenghua Hu
BACKGROUND: Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. PGRN is localized to the lysosome and important for proper lysosome function. However, the metabolism of PGRN in the lysosome is still unclear. RESULTS: Here, we report that PGRN is processed into ~10 kDa peptides intracellularly in multiple cell types and tissues and this processing is dependent on lysosomal activities...
August 23, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28828399/intracellular-proteolysis-of-progranulin-generates-stable-lysosomal-granulins-that-are-haploinsufficient-in-patients-with-frontotemporal-dementia-caused-by-grn-mutations
#19
Christopher J Holler, Georgia Taylor, Qiudong Deng, Thomas Kukar
Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain. PGRN is trafficked to the lysosome where its functional role is unknown. PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD-GRN mutation carriers...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28776681/another-piece-in-the-progranulin-puzzle-special-binding-between-progranulin-and-prosaposin-creates-additional-lysosomal-access-an-editorial-comment-for-the-interaction-between-progranulin-and-prosaposin-is-mediated-by-granulins-and-the-linker-region-between
#20
EDITORIAL
Philip Van Damme
Loss-of-function mutations in the gene encoding the growth factor progranulin cause degeneration of the ageing brain in a dose-dependent manner. While heterozygous mutations result in adult onset frontotemporal dementia, the much rarer homozygous null mutations cause an early onset lysosomal storage disorder. A better understanding of the biology of progranulin in the central nervous system is needed to find solutions for these incurable diseases. This Editorial highlights a study by Zhou et al. in the current issue of the Journal of Neurochemistry, in which the authors provide data that are a step towards this goal...
October 2017: Journal of Neurochemistry
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