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Hyosuk Cho, Gong-Qing Shen, Xiaofeng Wang, Fan Wang, Stephen Archacki, Yabo Li, Gang Yu, Susmita Chakrabarti, Qiuyun Chen, Qing Kenneth Wang
Coronary artery disease (CAD) is the leading cause of death worldwide. Long noncoding RNAs (lncRNAs) are a class of noncoding transcripts of > 200 nucleotides and are increasingly recognized as playing functional roles in physiology and disease. ANRIL is a lncRNA gene mapped to the chromosome 9p21 genetic locus for CAD identified by the first series of genome-wide association studies (GWAS). However, ANRIL's role in CAD and the underlying molecular mechanism are unknown. Here, we show that the major ANRIL transcript in endothelial cells (ECs) is DQ485454 with a much higher expression level in ECs than in THP-1 monocytes...
January 17, 2019: Journal of Biological Chemistry
Yoko Ito, Taila Hartley, Stephen Baird, Sunita Venkateswaran, Cas Simons, Nicole I Wolf, Kym M Boycott, David A Dyment, Kristin D Kernohan
No abstract text is available yet for this article.
December 2018: Neurology. Genetics
Keith A Josephs, Melissa E Murray, Nirubol Tosakulwong, Stephen D Weigand, Amanda M Serie, Ralph B Perkerson, Billie J Matchett, Clifford R Jack, David S Knopman, Ronald C Petersen, Joseph E Parisi, Leonard Petrucelli, Matthew Baker, Rosa Rademakers, Jennifer L Whitwell, Dennis W Dickson
TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with "typical" TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β)...
January 2, 2019: Acta Neuropathologica
Emma L Clayton, Carmelo Milioto, Bhavana Muralidharan, Frances E Norona, James R Edgar, Armand Soriano, Paymaan Jafar-Nejad, Frank Rigo, John Collinge, Adrian M Isaacs
Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia and lead to lysosomal storage pathology in neurons. We here report that physiological levels of mutant CHMP2B causes reduced numbers and significantly impaired trafficking of endolysosomes within neuronal dendrites, accompanied by increased dendritic branching. Mechanistically, this is due to the stable incorporation of mutant CHMP2B onto neuronal endolysosomes, which we show renders them unable to traffic within dendrites. This defect is due to the inability of mutant CHMP2B to recruit the ATPase VPS4, which is required for release of CHMP2B from endosomal membranes...
December 1, 2018: Brain: a Journal of Neurology
Jonathan D Cherry, Jesse Mez, John F Crary, Yorghos Tripodis, Victor E Alvarez, Ian Mahar, Bertrand R Huber, Michael L Alosco, Raymond Nicks, Bobak Abdolmohammadi, Patrick T Kiernan, Laney Evers, Sarah Svirsky, Katharine Babcock, Hannah M Gardner, Gaoyuan Meng, Christopher J Nowinski, Brett M Martin, Brigid Dwyer, Neil W Kowall, Robert C Cantu, Lee E Goldstein, Douglas I Katz, Robert A Stern, Lindsay A Farrer, Ann C McKee, Thor D Stein
The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia...
November 4, 2018: Acta Neuropathologica Communications
Jian Kang, Liangzhong Lim, Jianxing Song
TMEM106B was initially identified as a risk factor for FTLD, but recent studies highlighted its general role in neurodegenerative diseases. Very recently TMEM106B has also been characterized to regulate aging phenotypes. TMEM106B is a 274-residue lysosomal protein whose cytoplasmic domain functions in the endosomal/autophagy pathway by dynamically and transiently interacting with diverse categories of proteins but the underlying structural basis remains completely unknown. Here we conducted bioinformatics analysis and biophysical characterization by CD and NMR spectroscopy, and obtained results reveal that the TMEM106B cytoplasmic domain is intrinsically disordered with no well-defined three-dimensional structure...
2018: PloS One
Samrat T Kundu, Caitlin L Grzeskowiak, Jared J Fradette, Laura A Gibson, Leticia B Rodriguez, Chad J Creighton, Kenneth L Scott, Don L Gibbons
Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, therefore necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis. We recently performed an in vivo gain-of-function genetic screen to identify driver genes of lung cancer metastasis. In the study reported here, we identify TMEM106B as a primary robust driver of lung cancer metastasis. Ectopic expression of TMEM106B could significantly promote the synthesis of enlarged vesicular lysosomes that are laden with elevated levels of active cathepsins...
July 16, 2018: Nature Communications
Nimansha Jain, Alice S Chen-Plotkin
PURPOSE OF REVIEW: To review the evidence for genetic modifier effects in the neurodegenerative diseases Huntington's Disease (HD), Frontotemporal Lobar Degeneration (FTLD), Alzheimer's Disease (AD), and Parkinson's Disease (PD). RECENT FINDINGS: Increasingly, we understand human disease genetics less through the lens of single-locus/single-trait effects, and more through that of polygenic contributions to disease risk. In addition, specific examples of genetic modifier effects of the chromosome 7 gene TMEM106B on various target genes including those causal for Mendelian classes of FTLD - GRN and c9orf72 - have emerged from both genetic cohort studies and mechanistic examinations of biological pathways...
March 2018: Current Genetic Medicine Reports
Yingxue Ren, Marka van Blitterswijk, Mariet Allen, Minerva M Carrasquillo, Joseph S Reddy, Xue Wang, Thomas G Beach, Dennis W Dickson, Nilüfer Ertekin-Taner, Yan W Asmann, Rosa Rademakers
BACKGROUND: Single nucleotide polymorphisms (SNPs) inherited as one of two common haplotypes at the transmembrane protein 106B (TMEM106B) locus are associated with the risk of multiple neurodegenerative diseases, including frontotemporal lobar degeneration with pathological inclusions of TDP-43. Among the associated variants, rs3173615 (encoding p.T185S) is the only coding variant; however, non-coding variants may also contribute to disease risk. It has been reported that the risk haplotype is associated with higher levels of TMEM106B and increased levels of TMEM106B cause cytotoxicity; however, the precise mechanism through which TMEM106B haplotypes contribute to neurodegeneration is unclear...
July 3, 2018: Molecular Neurodegeneration
Andrew E Arrant, Alexandra M Nicholson, Xiaolai Zhou, Rosa Rademakers, Erik D Roberson
BACKGROUND: Loss of function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD). Progranulin is a secreted glycoprotein that localizes to lysosomes and is critical for proper lysosomal function. Heterozygous GRN mutation carriers develop FTD with TDP-43 pathology and exhibit signs of lysosomal dysfunction in the brain, with increased levels of lysosomal proteins and lipofuscin accumulation. Homozygous GRN mutation carriers develop neuronal ceroid lipofuscinosis (NCL), an earlier-onset lysosomal storage disorder caused by severe lysosomal dysfunction...
June 22, 2018: Molecular Neurodegeneration
Shunsuke Koga, Naomi Kouri, Ronald L Walton, Mark T W Ebbert, Keith A Josephs, Irene Litvan, Neill Graff-Radford, J Eric Ahlskog, Ryan J Uitti, Jay A van Gerpen, Bradley F Boeve, Adam Parks, Owen A Ross, Dennis W Dickson
Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43 kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43...
June 20, 2018: Acta Neuropathologica
Cyril Pottier, Xiaolai Zhou, Ralph B Perkerson, Matt Baker, Gregory D Jenkins, Daniel J Serie, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Adolfo López de Munain, Miren Zulaica, Fermin Moreno, Isabelle Le Ber, Florence Pasquier, Didier Hannequin, Raquel Sánchez-Valle, Anna Antonell, Albert Lladó, Tammee M Parsons, NiCole A Finch, Elizabeth C Finger, Carol F Lippa, Edward D Huey, Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Robert A Rissman, Jaroslaw Slawek, Emilia Sitek, Peter Johannsen, Jørgen E Nielsen, Yingxue Ren, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Elizabeth Christopher, Melissa E Murray, Kevin F Bieniek, Bret M Evers, Camilla Ferrari, Sara Rollinson, Anna Richardson, Elio Scarpini, Giorgio G Fumagalli, Alessandro Padovani, John Hardy, Parastoo Momeni, Raffaele Ferrari, Francesca Frangipane, Raffaele Maletta, Maria Anfossi, Maura Gallo, Leonard Petrucelli, EunRan Suh, Oscar L Lopez, Tsz H Wong, Jeroen G J van Rooij, Harro Seelaar, Simon Mead, Richard J Caselli, Eric M Reiman, Marwan Noel Sabbagh, Mads Kjolby, Anders Nykjaer, Anna M Karydas, Adam L Boxer, Lea T Grinberg, Jordan Grafman, Salvatore Spina, Adrian Oblak, M-Marsel Mesulam, Sandra Weintraub, Changiz Geula, John R Hodges, Olivier Piguet, William S Brooks, David J Irwin, John Q Trojanowski, Edward B Lee, Keith A Josephs, Joseph E Parisi, Nilüfer Ertekin-Taner, David S Knopman, Benedetta Nacmias, Irene Piaceri, Silvia Bagnoli, Sandro Sorbi, Marla Gearing, Jonathan Glass, Thomas G Beach, Sandra E Black, Mario Masellis, Ekaterina Rogaeva, Jean-Paul Vonsattel, Lawrence S Honig, Julia Kofler, Amalia C Bruni, Julie Snowden, David Mann, Stuart Pickering-Brown, Janine Diehl-Schmid, Juliane Winkelmann, Daniela Galimberti, Caroline Graff, Linn Öijerstedt, Claire Troakes, Safa Al-Sarraj, Carlos Cruchaga, Nigel J Cairns, Jonathan D Rohrer, Glenda M Halliday, John B Kwok, John C van Swieten, Charles L White, Bernardino Ghetti, Jill R Murell, Ian R A Mackenzie, Ging-Yuek R Hsiung, Barbara Borroni, Giacomina Rossi, Fabrizio Tagliavini, Zbigniew K Wszolek, Ronald C Petersen, Eileen H Bigio, Murray Grossman, Vivianna M Van Deerlin, William W Seeley, Bruce L Miller, Neill R Graff-Radford, Bradley F Boeve, Dennis W Dickson, Joanna M Biernacka, Rosa Rademakers
BACKGROUND: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. METHODS: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data...
June 2018: Lancet Neurology
S Koga, W-L Lin, R L Walton, O A Ross, D W Dickson
AIMS: This study aimed to assess clinicopathologic features of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and its risk factors in multiple system atrophy (MSA). METHODS: Paraffin-embedded sections of the amygdala and basal forebrain from 186 autopsy-confirmed MSA cases were screened with immunohistochemistry for phospho-TDP-43. In cases having TDP-43 pathology, additional brain regions were assessed. Immunohistochemical and immunofluorescence double-staining and immunogold electron microscopy (IEM) were performed to evaluate colocalization of TDP-43 and α-synuclein...
December 2018: Neuropathology and Applied Neurobiology
Cas Simons, David Dyment, Marjo S van der Knaap, Nicole I Wolf
No abstract text is available yet for this article.
May 1, 2018: Brain: a Journal of Neurology
Huifang Yan, Thomas Kubisiak, Haoran Ji, Jiangxi Xiao, Jingmin Wang, Margit Burmeister
No abstract text is available yet for this article.
May 1, 2018: Brain: a Journal of Neurology
Xiaolai Zhou, Rosa Rademakers
No abstract text is available yet for this article.
December 1, 2017: Brain: a Journal of Neurology
Cas Simons, David Dyment, Stephen J Bent, Joanna Crawford, Marc D'Hooghe, Alfried Kohlschütter, Sunita Venkateswaran, Guy Helman, Bwee-Tien Poll-The, Christine C Makowski, Yoko Ito, Kristin Kernohan, Taila Hartley, Quinten Waisfisz, Ryan J Taft, Marjo S van der Knaap, Nicole I Wolf
Hypomyelinating leukodystrophies are a heterogeneous group of disorders with a clinical presentation that often includes early-onset nystagmus, ataxia and spasticity and a wide range of severity. Using next-generation sequencing techniques and GeneMatcher, we identified four unrelated patients with brain hypomyelination, all with the same recurrent dominant mutation, c.754G>A p.(Asp252Asn), in TMEM106B. The mutation was confirmed as de novo in three of the cases, and the mildly affected father of the fourth affected individual was confirmed as mosaic for this variant...
December 1, 2017: Brain: a Journal of Neurology
Daniela Galimberti, Giorgio G Fumagalli, Chiara Fenoglio, Sara M G Cioffi, Andrea Arighi, Maria Serpente, Barbara Borroni, Alessandro Padovani, Fabrizio Tagliavini, Mario Masellis, Maria Carmela Tartaglia, John van Swieten, Lieke Meeter, Caroline Graff, Alexandre de Mendonça, Martina Bocchetta, Jonathan D Rohrer, Elio Scarpini
We investigated whether progranulin plasma levels are predictors of the presence of progranulin gene (GRN) null mutations or of the development of symptoms in asymptomatic at risk members participating in the Genetic Frontotemporal Dementia Initiative, including 19 patients, 64 asymptomatic carriers, and 77 noncarriers. In addition, we evaluated a possible role of TMEM106B rs1990622 as a genetic modifier and correlated progranulin plasma levels and gray-matter atrophy. Plasma progranulin mean ± SD plasma levels in patients and asymptomatic carriers were significantly decreased compared with noncarriers (30...
February 2018: Neurobiology of Aging
Michael D Gallagher, Marijan Posavi, Peng Huang, Travis L Unger, Yosef Berlyand, Analise L Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D Wells, Struan F A Grant, Gerd A Blobel, Christopher D Brown, Alice S Chen-Plotkin
Neurodegenerative diseases pose an extraordinary threat to the world's aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain...
November 2, 2017: American Journal of Human Genetics
Nina Rostgaard, Peter Roos, Esben Budtz-Jørgensen, Peter Johannsen, Gunhild Waldemar, Anne Nørremølle, Suzanne G Lindquist, Susanne Gydesen, Jeremy M Brown, John Collinge, Adrian M Isaacs, Troels T Nielsen, Jørgen E Nielsen
Single-nucleotide polymorphisms in the TMEM106B gene have been identified as a risk factor in frontotemporal dementia (FTD). The major allele of SNP rs3173615 is a risk factor in sporadic FTD, whereas the minor allele seems protective in GRN- and C9orf72-mediated FTD. The role of apolipoprotein E (ApoE) in FTD is uncertain, though an established risk factor in Alzheimer's disease. In a unique Danish family, inherited FTD is caused by a mutation in the CHMP2B gene located on chromosome 3 (FTD-3). In this family, both risk factors TMEM106B and ApoE were analyzed and correlated to age at onset (AAO) and progression in terms of age at institutionalization (AAI) and age at death (AAD)...
November 2017: Neurobiology of Aging
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