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Acta Neuropathologica

André B Silveira, Lawryn H Kasper, Yiping Fan, Hongjian Jin, Gang Wu, Timothy I Shaw, Xiaoyan Zhu, Jon D Larson, John Easton, Ying Shao, Donald A Yergeau, Celeste Rosencrance, Kristy Boggs, Michael C Rusch, Liang Ding, Junyuan Zhang, David Finkelstein, Rachel M Noyes, Brent L Russell, Beisi Xu, Alberto Broniscer, Cynthia Wetmore, Stanley B Pounds, David W Ellison, Jinghui Zhang, Suzanne J Baker
Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Comparisons of matched DIPG xenografts with and without K27M knockdown allowed identification of mutation-specific effects on the transcriptome and epigenome...
February 15, 2019: Acta Neuropathologica
Shon A Koren, Matthew J Hamm, Shelby E Meier, Blaine E Weiss, Grant K Nation, Emad A Chishti, Juan Pablo Arango, Jing Chen, Haining Zhu, Eric M Blalock, Jose F Abisambra
There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels...
February 13, 2019: Acta Neuropathologica
Yanghao Hou, Jorge Pinheiro, Felix Sahm, David E Reuss, Daniel Schrimpf, Damian Stichel, Belén Casalini, Christian Koelsche, Philipp Sievers, Annika K Wefers, Annekathrin Reinhardt, Azadeh Ebrahimi, Francisco Fernández-Klett, Stefan Pusch, Jochen Meier, Leonille Schweizer, Werner Paulus, Marco Prinz, Christian Hartmann, Karl H Plate, Guido Reifenberger, Torsten Pietsch, Pascale Varlet, Mélanie Pagès, Ulrich Schüller, David Scheie, Karin de Stricker, Stephan Frank, Jürgen Hench, Bianca Pollo, Sebastian Brandner, Andreas Unterberg, Stefan M Pfister, David T W Jones, Andrey Korshunov, Wolfgang Wick, David Capper, Ingmar Blümcke, Andreas von Deimling, Luca Bertero
Papillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently, SLC44A1-PRKCA fusions have been described in PGNT. We subjected 28 brain tumors from different institutions histologically diagnosed as PGNT to molecular and morphological analysis. Array-based methylation analysis revealed that 17/28 tumors exhibited methylation profiles typical for other tumor entities, mostly dysembryoplastic neuroepithelial tumor and hemispheric pilocytic astrocytoma...
February 13, 2019: Acta Neuropathologica
Alberto Delaidelli, Asad Jan, Jochen Herms, Poul H Sorensen
Messenger RNA (mRNA) translation is the terminal step in protein synthesis, providing a crucial regulatory checkpoint for this process. Translational control allows specific cell types to respond to rapid changes in the microenvironment or to serve specific functions. For example, neurons use mRNA transport to achieve local protein synthesis at significant distances from the nucleus, the site of RNA transcription. Altered expression or functions of the various components of the translational machinery have been linked to several pathologies in the central nervous system...
February 9, 2019: Acta Neuropathologica
Cyril Pottier, Yingxue Ren, Ralph B Perkerson, Matt Baker, Gregory D Jenkins, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Jeroen G J van Rooij, Melissa E Murray, Elizabeth Christopher, Shannon K McDonnell, Zachary Fogarty, Anthony Batzler, Shulan Tian, Cristina T Vicente, Billie Matchett, Anna M Karydas, Ging-Yuek Robin Hsiung, Harro Seelaar, Merel O Mol, Elizabeth C Finger, Caroline Graff, Linn Öijerstedt, Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Johannes Prudlo, Patrizia Rizzu, Javier Simon-Sanchez, Dieter Edbauer, Sigrun Roeber, Janine Diehl-Schmid, Bret M Evers, Andrew King, M Marsel Mesulam, Sandra Weintraub, Changiz Geula, Kevin F Bieniek, Leonard Petrucelli, Geoffrey L Ahern, Eric M Reiman, Bryan K Woodruff, Richard J Caselli, Edward D Huey, Martin R Farlow, Jordan Grafman, Simon Mead, Lea T Grinberg, Salvatore Spina, Murray Grossman, David J Irwin, Edward B Lee, EunRan Suh, Julie Snowden, David Mann, Nilufer Ertekin-Taner, Ryan J Uitti, Zbigniew K Wszolek, Keith A Josephs, Joseph E Parisi, David S Knopman, Ronald C Petersen, John R Hodges, Olivier Piguet, Ethan G Geier, Jennifer S Yokoyama, Robert A Rissman, Ekaterina Rogaeva, Julia Keith, Lorne Zinman, Maria Carmela Tartaglia, Nigel J Cairns, Carlos Cruchaga, Bernardino Ghetti, Julia Kofler, Oscar L Lopez, Thomas G Beach, Thomas Arzberger, Jochen Herms, Lawrence S Honig, Jean Paul Vonsattel, Glenda M Halliday, John B Kwok, Charles L White, Marla Gearing, Jonathan Glass, Sara Rollinson, Stuart Pickering-Brown, Jonathan D Rohrer, John Q Trojanowski, Vivianna Van Deerlin, Eileen H Bigio, Claire Troakes, Safa Al-Sarraj, Yan Asmann, Bruce L Miller, Neill R Graff-Radford, Bradley F Boeve, William W Seeley, Ian R A Mackenzie, John C van Swieten, Dennis W Dickson, Joanna M Biernacka, Rosa Rademakers
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively...
February 9, 2019: Acta Neuropathologica
Sylvia E Perez, Jennifer C Miguel, Bin He, Michael Malek-Ahmadi, Eric E Abrahamson, Milos D Ikonomovic, Ira Lott, Eric Doran, Melissa J Alldred, Stephen D Ginsberg, Elliott J Mufson
Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD -) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD - cases...
February 7, 2019: Acta Neuropathologica
Philippe Bourassa, Cyntia Tremblay, Julie A Schneider, David A Bennett, Frédéric Calon
Several pieces of evidence suggest that blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD), exemplified by the frequent occurrence of cerebral amyloid angiopathy (CAA) and the defective clearance of Aβ peptides. However, the specific role of brain microvascular cells in these anomalies remains elusive. In this study, we validated by Western, ELISA and immunofluorescence analyses a procedure to generate microvasculature-enriched fractions from frozen samples of human cerebral cortex...
February 7, 2019: Acta Neuropathologica
Ilie-Cosmin Stancu, Niels Cremers, Hannah Vanrusselt, Julien Couturier, Alexandre Vanoosthuyse, Sofie Kessels, Chritica Lodder, Bert Brône, François Huaux, Jean-Noël Octave, Dick Terwel, Ilse Dewachter
Brains of Alzheimer's disease patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, both invariably associated with neuroinflammation. A crucial role for NLRP3-ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3-ASC inflammasome (Halle et al. in Nat Immunol 9:857-865, 2008) and conversely NLRP3-ASC inflammasome activation exacerbates amyloid pathology in vivo (Heneka et al...
February 5, 2019: Acta Neuropathologica
Lien Veys, Marjan Vandenabeele, Isabel Ortuño-Lizarán, Veerle Baekelandt, Nicolás Cuenca, Lieve Moons, Lies De Groef
Despite decades of research, accurate diagnosis of Parkinson's disease remains a challenge, and disease-modifying treatments are still lacking. Research into the early (presymptomatic) stages of Parkinson's disease and the discovery of novel biomarkers is of utmost importance to reduce this burden and to come to a more accurate diagnosis at the very onset of the disease. Many have speculated that non-motor symptoms could provide a breakthrough in the quest for early biomarkers of Parkinson's disease, including the visual disturbances and retinal abnormalities that are seen in the majority of Parkinson's disease patients...
February 5, 2019: Acta Neuropathologica
Katja Burk, R Jeroen Pasterkamp
Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease caused by degeneration of motor neurons in the brain and spinal cord leading to muscle weakness. Median survival after symptom onset in patients is 3-5 years and no effective therapies are available to treat or cure ALS. Therefore, further insight is needed into the molecular and cellular mechanisms that cause motor neuron degeneration and ALS. Different ALS disease mechanisms have been identified and recent evidence supports a prominent role for defects in intracellular transport...
February 5, 2019: Acta Neuropathologica
Hiroaki Sekiya, Hisatomo Kowa, Hinako Koga, Mariko Takata, Wataru Satake, Naonobu Futamura, Itaru Funakawa, Kenji Jinnai, Motonori Takahashi, Takeshi Kondo, Yasuhiro Ueno, Motoi Kanagawa, Kazuhiro Kobayashi, Tatsushi Toda
Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA...
February 5, 2019: Acta Neuropathologica
Rob Vogels, Nicolas Macagno, Klaus Griewank, Patricia Groenen, Marian Verdijk, Judy Fonville, Benno Kusters, Dominique Figarella-Branger, Pieter Wesseling, Corinne Bouvier, Uta Flucke
No abstract text is available yet for this article.
February 2, 2019: Acta Neuropathologica
Stephen A Semick, Rahul A Bharadwaj, Leonardo Collado-Torres, Ran Tao, Joo Heon Shin, Amy Deep-Soboslay, James R Weiss, Daniel R Weinberger, Thomas M Hyde, Joel E Kleinman, Andrew E Jaffe, Venkata S Mattay
Late-onset Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identified 858 sites with robust differential methylation collectively annotated to 772 possible genes (FDR < 5%, within 10 kb)...
February 2, 2019: Acta Neuropathologica
Xavière Lornage, Norma B Romero, Claire A Grosgogeat, Edoardo Malfatti, Sandra Donkervoort, Michael M Marchetti, Sarah B Neuhaus, A Reghan Foley, Clémence Labasse, Raphaël Schneider, Robert Y Carlier, Katherine R Chao, Livija Medne, Jean-François Deleuze, David Orlikowski, Carsten G Bönnemann, Vandana A Gupta, Michel Fardeau, Johann Böhm, Jocelyn Laporte
The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines...
January 30, 2019: Acta Neuropathologica
Amanda L Woerman, Abby Oehler, Sabeen A Kazmi, Jisoo Lee, Glenda M Halliday, Lefkos T Middleton, Steve M Gentleman, Daniel A Mordes, Salvatore Spina, Lea T Grinberg, Steven H Olson, Stanley B Prusiner
Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/- , which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson's disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA+/+ )Nbm, Tg(SNCA*A30P+/+ )Nbm, and Tg(SNCA*A53T+/+ )Nbm]...
January 28, 2019: Acta Neuropathologica
Olubankole Aladesuyi Arogundade, Jennifer E Stauffer, Shahram Saberi, Sandra Diaz-Garcia, Sahana Malik, Hani Basilim, Maria J Rodriguez, Takuya Ohkubo, John Ravits
No abstract text is available yet for this article.
January 21, 2019: Acta Neuropathologica
Anna R Tröscher, Isabella Wimmer, Lucía Quemada-Garrido, Ulrike Köck, Denise Gessl, Sanne G S Verberk, Bethany Martin, Hans Lassmann, Christian G Bien, Jan Bauer
Microglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. In RE stage 0, small primary microglia nodules could be identified in the absence of T cells. These primary nodules showed inflammasome activation and endosomal Toll-like receptor upregulation...
January 20, 2019: Acta Neuropathologica
Julieann C Lee, Javier E Villanueva-Meyer, Sean P Ferris, Emily A Sloan, Jeffrey W Hofmann, Eyas M Hattab, Brian J Williams, Hua Guo, Joseph Torkildson, Adriana Florez, Jessica Van Ziffle, Courtney Onodera, James P Grenert, Soo-Jin Cho, Andrew E Horvai, David T W Jones, Stefan M Pfister, Christian Koelsche, Andreas von Deimling, Andrey Korshunov, Arie Perry, David A Solomon
No abstract text is available yet for this article.
January 16, 2019: Acta Neuropathologica
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
Thomas G Moens, Teresa Niccoli, Katherine M Wilson, Magda L Atilano, Nicol Birsa, Lauren M Gittings, Benedikt V Holbling, Miranda C Dyson, Annora Thoeng, Jacob Neeves, Idoia Glaria, Lu Yu, Julia Bussmann, Erik Storkebaum, Mercedes Pardo, Jyoti S Choudhary, Pietro Fratta, Linda Partridge, Adrian M Isaacs
A GGGGCC hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense repeat-containing transcripts undergo repeat-associated non-AUG-initiated translation to produce five dipeptide proteins (DPRs). The polyGR and polyPR DPRs are extremely toxic when expressed in Drosophila neurons. To determine the mechanism that mediates this toxicity, we purified DPRs from the Drosophila brain and used mass spectrometry to identify the in vivo neuronal DPR interactome...
January 2, 2019: Acta Neuropathologica
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