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Tar DNA-binding protein 43 progranulin

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https://www.readbyqxmd.com/read/27543771/survival-in-the-pre-senile-dementia-frontotemporal-lobar-degeneration-with-tdp-43-proteinopathy-effects-of-genetic-demographic-and-neuropathological-variables
#1
R A Armstrong
Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight...
2016: Folia Neuropathologica
https://www.readbyqxmd.com/read/27543298/what-we-know-about-tmem106b-in-neurodegeneration
#2
REVIEW
Alexandra M Nicholson, Rosa Rademakers
Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7...
November 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/26791154/asymmetric-pathology-in-primary-progressive-aphasia-with-progranulin-mutations-and-tdp-inclusions
#3
Garam Kim, Saman S Ahmadian, Melanie Peterson, Zach Parton, Rohail Memon, Sandra Weintraub, Alfred Rademaker, Eileen Bigio, M-Marsel Mesulam, Changiz Geula
OBJECTIVE: To investigate quantitative regional distribution and hemispheric asymmetry of TDP-43 (TAR DNA-binding protein 43) inclusions, neurons, and activated microglia in primary progressive aphasia (PPA) with progranulin (GRN) mutations, and to determine concordance between distribution of pathology, clinical phenotype, and known atrophy patterns. METHODS: Antibodies to phospho-TDP-43, NeuN (neuronal nuclei), and HLA-DR were used to visualize inclusions, neurons, and activated microglia in paraffin-embedded tissue sections from 4 participants with PPA: 2 of the agrammatic and 2 of the logopenic subtype...
February 16, 2016: Neurology
https://www.readbyqxmd.com/read/26624524/progranulin-deficiency-induces-overactivation-of-wnt5a-expression-via-tnf-%C3%AE-nf-%C3%AE%C2%BAb-pathway-in-peripheral-cells-from-frontotemporal-dementia-linked-granulin-mutation-carriers
#4
Carolina Alquézar, Ana de la Encarnación, Fermín Moreno, Adolfo López de Munain, Ángeles Martín-Requero
BACKGROUND: Loss-of-function progranulin gene (GRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein 43 (TDP-43) pathology (frontotemporal lobar degeneration [FTLD]-TDP); however, little is known about the association between progranulin (PGRN) deficiency and neuronal loss in individuals with FTLD-TDP. Previously we reported enhanced proliferative activity associated with the activation of WNT5A/CDK6/pRb signalling in PGRN-deficient cells...
June 2016: Journal of Psychiatry & Neuroscience: JPN
https://www.readbyqxmd.com/read/26555887/investigating-the-role-of-filamin-c-in-belgian-patients-with-frontotemporal-dementia-linked-to-grn-deficiency-in-ftld-tdp-brains
#5
Jonathan Janssens, Stéphanie Philtjens, Gernot Kleinberger, Sara Van Mossevelde, Julie van der Zee, Rita Cacace, Sebastiaan Engelborghs, Anne Sieben, Julia Banzhaf-Strathmann, Lubina Dillen, Céline Merlin, Ivy Cuijt, Caroline Robberecht, Bettina Schmid, Patrick Santens, Adrian Ivanoiu, Mathieu Vandenbulcke, Rik Vandenberghe, Patrick Cras, Peter P De Deyn, Jean-Jacques Martin, Stuart Maudsley, Christian Haass, Marc Cruts, Christine Van Broeckhoven
TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals...
2015: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/26388768/phenotypic-heterogeneity-of-monogenic-frontotemporal-dementia
#6
REVIEW
Alberto Benussi, Alessandro Padovani, Barbara Borroni
Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD-MND)...
2015: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/25943890/whole-genome-sequencing-reveals-important-role-for-tbk1-and-optn-mutations-in-frontotemporal-lobar-degeneration-without-motor-neuron-disease
#7
Cyril Pottier, Kevin F Bieniek, NiCole Finch, Maartje van de Vorst, Matt Baker, Ralph Perkersen, Patricia Brown, Thomas Ravenscroft, Marka van Blitterswijk, Alexandra M Nicholson, Michael DeTure, David S Knopman, Keith A Josephs, Joseph E Parisi, Ronald C Petersen, Kevin B Boylan, Bradley F Boeve, Neill R Graff-Radford, Joris A Veltman, Christian Gilissen, Melissa E Murray, Dennis W Dickson, Rosa Rademakers
Frontotemporal lobar degeneration with TAR DNA-binding protein 43 inclusions (FTLD-TDP) is the most common pathology associated with frontotemporal dementia (FTD). Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) and mutations in progranulin (GRN) are the major known genetic causes of FTLD-TDP; however, the genetic etiology in the majority of FTLD-TDP remains unexplained. In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for C9ORF72 and GRN mutations and report on the contribution of rare single nucleotide and copy number variants in 21 known neurodegenerative disease genes...
July 2015: Acta Neuropathologica
https://www.readbyqxmd.com/read/25838514/multiple-therapeutic-effects-of-progranulin-on-experimental-acute-ischaemic-stroke
#8
Masato Kanazawa, Kunio Kawamura, Tetsuya Takahashi, Minami Miura, Yoshinori Tanaka, Misaki Koyama, Masafumi Toriyabe, Hironaka Igarashi, Tsutomu Nakada, Masugi Nishihara, Masatoyo Nishizawa, Takayoshi Shimohata
In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia...
July 2015: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/25155018/early-retinal-neurodegeneration-and-impaired-ran-mediated-nuclear-import-of-tdp-43-in-progranulin-deficient-ftld
#9
Michael E Ward, Alice Taubes, Robert Chen, Bruce L Miller, Chantelle F Sephton, Jeffrey M Gelfand, Sakura Minami, John Boscardin, Lauren Herl Martens, William W Seeley, Gang Yu, Joachim Herz, Anthony J Filiano, Andrew E Arrant, Erik D Roberson, Timothy W Kraft, Robert V Farese, Ari Green, Li Gan
Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice...
September 22, 2014: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/25056957/progranulin-transcripts-with-short-and-long-5-untranslated-regions-utrs-are-differentially-expressed-via-posttranscriptional-and-translational-repression
#10
Anja Capell, Katrin Fellerer, Christian Haass
Frontotemporal lobar degeneration is associated with cytoplasmic or nuclear deposition of the TAR DNA-binding protein 43 (TDP-43). Haploinsufficiency of progranulin (GRN) is a major genetic risk factor for frontotemporal lobar degeneration associated with TDP-43 deposition. Therefore, understanding the mechanisms that control cellular expression of GRN is required not only to understand disease etiology but also for the development of potential therapeutic strategies. We identified different GRN transcripts with short (38-93 nucleotides) or long (219 nucleotides) 5' UTRs and demonstrate a cellular mechanism that represses translation of GRN mRNAs with long 5' UTRs...
September 12, 2014: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/25022663/possible-involvement-of-lysosomal-dysfunction-in-pathological-changes-of-the-brain-in-aged-progranulin-deficient-mice
#11
Yoshinori Tanaka, James K Chambers, Takashi Matsuwaki, Keitaro Yamanouchi, Masugi Nishihara
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...
2014: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/24709683/a-novel-grn-mutation-grn-c-708-6_-9deltgag-in-frontotemporal-lobar-degeneration-with-tdp-43-positive-inclusions-clinicopathologic-report-of-6-cases
#12
Esther N Bit-Ivan, Eunran Suh, Hyung-Sub Shim, Sandra Weintraub, Bradley T Hyman, Steven E Arnold, Elisabeth McCarty-Wood, Viviana M Van Deerlin, Julie A Schneider, John Q Trojanowski, Matthew P Frosch, Matt C Baker, Rosa Rademakers, Marsel Mesulam, Eileen H Bigio
Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene...
May 2014: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/24684749/tmem106b-expression-is-reduced-in-alzheimer-s-disease-brains
#13
Jun-Ichi Satoh, Yoshihiro Kino, Natsuki Kawana, Yoji Yamamoto, Tsuyoshi Ishida, Yuko Saito, Kunimasa Arima
INTRODUCTION: TMEM106B is a transmembrane glycoprotein of unknown function located within endosome/lysosome compartments expressed ubiquitously in various cell types. Previously, the genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), particularly in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations...
2014: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/24619111/common-pathobiochemical-hallmarks-of-progranulin-associated-frontotemporal-lobar-degeneration-and-neuronal-ceroid-lipofuscinosis
#14
Julia K Götzl, Kohji Mori, Markus Damme, Katrin Fellerer, Sabina Tahirovic, Gernot Kleinberger, Jonathan Janssens, Julie van der Zee, Christina M Lang, Elisabeth Kremmer, Jean-Jacques Martin, Sebastiaan Engelborghs, Hans A Kretzschmar, Thomas Arzberger, Christine Van Broeckhoven, Christian Haass, Anja Capell
Heterozygous loss-of-function mutations in the progranulin (GRN) gene and the resulting reduction of GRN levels is a common genetic cause for frontotemporal lobar degeneration (FTLD) with accumulation of TAR DNA-binding protein (TDP)-43. Recently, it has been shown that a complete GRN deficiency due to a homozygous GRN loss-of-function mutation causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. These findings suggest that lysosomal dysfunction may also contribute to some extent to FTLD...
2014: Acta Neuropathologica
https://www.readbyqxmd.com/read/24494724/cortical-degeneration-in-frontotemporal-lobar-degeneration-with-tdp-43-proteinopathy-caused-by-progranulin-gene-mutation
#15
Richard A Armstrong
Familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is most commonly caused by progranulin (GRN) gene mutation. To characterize cortical degeneration in these cases, changes in density of the pathology across the cortical laminae of the frontal and temporal lobe were studied in seven cases of FTLD-TDP with GRN mutation using quantitative analysis and polynomial curve fitting. In 50% of gyri studied, neuronal cytoplasmic inclusions (NCI) exhibited a peak of density in the upper cortical laminae...
December 2014: International Journal of Neuroscience
https://www.readbyqxmd.com/read/24442578/tmem106b-is-a-genetic-modifier-of-frontotemporal-lobar-degeneration-with-c9orf72-hexanucleotide-repeat-expansions
#16
MULTICENTER STUDY
Michael D Gallagher, Eunran Suh, Murray Grossman, Lauren Elman, Leo McCluskey, John C Van Swieten, Safa Al-Sarraj, Manuela Neumann, Ellen Gelpi, Bernardino Ghetti, Jonathan D Rohrer, Glenda Halliday, Christine Van Broeckhoven, Danielle Seilhean, Pamela J Shaw, Matthew P Frosch, Irina Alafuzoff, Anna Antonell, Nenad Bogdanovic, William Brooks, Nigel J Cairns, Johnathan Cooper-Knock, Carl Cotman, Patrick Cras, Marc Cruts, Peter P De Deyn, Charles DeCarli, Carol Dobson-Stone, Sebastiaan Engelborghs, Nick Fox, Douglas Galasko, Marla Gearing, Ilse Gijselinck, Jordan Grafman, Päivi Hartikainen, Kimmo J Hatanpaa, J Robin Highley, John Hodges, Christine Hulette, Paul G Ince, Lee-Way Jin, Janine Kirby, Julia Kofler, Jillian Kril, John B J Kwok, Allan Levey, Andrew Lieberman, Albert Llado, Jean-Jacques Martin, Eliezer Masliah, Christopher J McDermott, Ann McKee, Catriona McLean, Simon Mead, Carol A Miller, Josh Miller, David G Munoz, Jill Murrell, Henry Paulson, Olivier Piguet, Martin Rossor, Raquel Sanchez-Valle, Mary Sano, Julie Schneider, Lisa C Silbert, Salvatore Spina, Julie van der Zee, Tim Van Langenhove, Jason Warren, Stephen B Wharton, Charles L White, Randall L Woltjer, John Q Trojanowski, Virginia M Y Lee, Vivianna Van Deerlin, Alice S Chen-Plotkin
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease...
March 2014: Acta Neuropathologica
https://www.readbyqxmd.com/read/24385136/tmem106b-protects-c9orf72-expansion-carriers-against-frontotemporal-dementia
#17
MULTICENTER STUDY
Marka van Blitterswijk, Bianca Mullen, Alexandra M Nicholson, Kevin F Bieniek, Michael G Heckman, Matthew C Baker, Mariely DeJesus-Hernandez, Nicole A Finch, Patricia H Brown, Melissa E Murray, Ging-Yuek R Hsiung, Heather Stewart, Anna M Karydas, Elizabeth Finger, Andrew Kertesz, Eileen H Bigio, Sandra Weintraub, Marsel Mesulam, Kimmo J Hatanpaa, Charles L White, Michael J Strong, Thomas G Beach, Zbigniew K Wszolek, Carol Lippa, Richard Caselli, Leonard Petrucelli, Keith A Josephs, Joseph E Parisi, David S Knopman, Ronald C Petersen, Ian R Mackenzie, William W Seeley, Lea T Grinberg, Bruce L Miller, Kevin B Boylan, Neill R Graff-Radford, Bradley F Boeve, Dennis W Dickson, Rosa Rademakers
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays...
March 2014: Acta Neuropathologica
https://www.readbyqxmd.com/read/24252750/expression-of-tmem106b-the-frontotemporal-lobar-degeneration-associated-protein-in-normal-and-diseased-human-brain
#18
COMPARATIVE STUDY
Johanna I Busch, Maria Martinez-Lage, Emily Ashbridge, Murray Grossman, Vivianna M Van Deerlin, Fenghua Hu, Virginia M Y Lee, John Q Trojanowski, Alice S Chen-Plotkin
BACKGROUND: Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP...
2013: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/23759146/novel-progranulin-variants-do-not-disrupt-progranulin-secretion-and-cleavage
#19
Celeste M Karch, Amanda T Jeng, Tara Skorupa, Carlos Cruchaga, Alison M Goate
A subset of frontotemporal dementia cases are neuropathologically defined by tau-negative, TAR DNA-binding protein-43, and ubiquitin-positive inclusions in the brain and are associated with mutations in the progranulin gene (GRN). Deep sequencing of families exhibiting late-onset dementia revealed several novel variants in GRN. Because of the small size of these families and limited availability of samples, it was not possible to determine whether the variants segregated with the disease. Furthermore, none of these families had autopsy confirmation of diagnosis...
November 2013: Neurobiology of Aging
https://www.readbyqxmd.com/read/23742080/tmem106b-p-t185s-regulates-tmem106b-protein-levels-implications-for-frontotemporal-dementia
#20
Alexandra M Nicholson, Nicole A Finch, Aleksandra Wojtas, Matt C Baker, Ralph B Perkerson, Monica Castanedes-Casey, Linda Rousseau, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Ging-Yuek R Hsiung, Ian R Mackenzie, Elizabeth Finger, Bradley F Boeve, Nilüfer Ertekin-Taner, Neill R Graff-Radford, Dennis W Dickson, Rosa Rademakers
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD-TDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations...
September 2013: Journal of Neurochemistry
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