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Acta Neuropathologica Communications

Angela N Viaene, Mariarita Santi, Jason Rosenbaum, Marilyn M Li, Lea F Surrey, MacLean P Nasrallah
Mutations in SETD2 are found in many tumors, including central nervous system (CNS) tumors. Previous work has shown these mutations occur specifically in high grade gliomas of the cerebral hemispheres in pediatric and young adult patients. We investigated SETD2 mutations in a cohort of approximately 640 CNS tumors via next generation sequencing; 23 mutations were detected across 19 primary CNS tumors. Mutations were found in a wide variety of tumors and locations at a broad range of allele frequencies. SETD2 mutations were seen in both low and high grade gliomas as well as non-glial tumors, and occurred in patients greater than 55 years of age, in addition to pediatric and young adult patients...
November 12, 2018: Acta Neuropathologica Communications
Tianhong Chen, Bo Huang, Xinglong Shi, Limo Gao, Cao Huang
Mutations in ubiquilin2 (UBQLN2) have been linked to abnormal protein aggregation in amyotrophic lateral sclerosis (ALS). The mechanisms underlying UBQLN2-related neurodegenerative diseases remain unclear. Using a tetracycline-regulated gene expression system, the ALS-linked UBQLN2P497H mutant was selectively expressed in either the spinal motor neurons or astrocytes in rats. We found that selectively expressing mutant UBQLN2P497H in the spinal motor neurons caused several core features of ALS, including the progressive degeneration of motor neurons, the denervation atrophy of skeletal muscles, and the abnormal protein accumulation...
November 8, 2018: Acta Neuropathologica Communications
Justin W Nicholatos, Adam B Francisco, Carolyn A Bender, Tiffany Yeh, Fraz J Lugay, Jairo E Salazar, Christin Glorioso, Sergiy Libert
Parkinson's disease is characterized by progressive death of dopaminergic neurons, leading to motor and cognitive dysfunction. Epidemiological studies consistently show that the use of tobacco reduces the risk of Parkinson's. We report that nicotine reduces the abundance of SIRT6 in neuronal culture and brain tissue. We find that reduction of SIRT6 is partly responsible for neuroprotection afforded by nicotine. Additionally, SIRT6 abundance is greater in Parkinson's patient brains, and decreased in the brains of tobacco users...
November 8, 2018: Acta Neuropathologica Communications
Shaomin Li, Ming Jin, Lei Liu, Yifan Dang, Beth L Ostaszewski, Dennis J Selkoe
Pathologic, biochemical and genetic evidence indicates that accumulation and aggregation of amyloid β-proteins (Aβ) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Several therapeutic interventions attempting to lower Aβ have failed to ameliorate cognitive decline in patients with clinical AD significantly, but most such approaches target only one or two facets of Aβ production/clearance/toxicity and do not consider the heterogeneity of human Aβ species. As synaptic dysfunction may be among the earliest deficits in AD, we used hippocampal long-term potentiation (LTP) as a sensitive indicator of the early neurotoxic effects of Aβ species...
November 8, 2018: Acta Neuropathologica Communications
Gerben J Schaaf, Tom J M van Gestel, Stijn L M In 't Groen, Bart de Jong, Björn Boomaars, Antonietta Tarallo, Monica Cardone, Giancarlo Parenti, Ans T van der Ploeg, W W M Pim Pijnappel
Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa-/- satellite cells to regenerate muscle damage...
November 7, 2018: Acta Neuropathologica Communications
David Castel, Cathy Philippe, Thomas Kergrohen, Martin Sill, Jane Merlevede, Emilie Barret, Stéphanie Puget, Christian Sainte-Rose, Christof M Kramm, Chris Jones, Pascale Varlet, Stefan M Pfister, Jacques Grill, David T W Jones, Marie-Anne Debily
Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG...
November 5, 2018: Acta Neuropathologica Communications
Melissa M Blessing, Patrick R Blackburn, Jessica R Balcom, Chandra Krishnan, Virginia L Harrod, Michael T Zimmermann, Emily G Barr Fritcher, Christopher D Zysk, Rory A Jackson, Asha A Nair, Robert B Jenkins, Kevin C Halling, Benjamin R Kipp, Cristiane M Ida
No abstract text is available yet for this article.
November 5, 2018: Acta Neuropathologica Communications
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
Lydie Lagalice, Julien Pichon, Eliot Gougeon, Salwa Soussi, Johan Deniaud, Mireille Ledevin, Virginie Maurier, Isabelle Leroux, Sylvie Durand, Carine Ciron, Francesca Franzoso, Laurence Dubreil, Thibaut Larcher, Karl Rouger, Marie-Anne Colle
Pompe disease, which is due to acid alpha-glucosidase deficiency, is characterized by skeletal muscle dysfunction attributed to the accumulation of glycogen-filled lysosomes and autophagic buildup. Despite the extensive tissue damages, a failure of satellite cell (SC) activation and lack of muscle regeneration have been reported in patients. However, the origin of this defective program is unknown. Additionally, whether these deficits occur gradually over the disease course is unclear. Using a longitudinal pathophysiological study of two muscles in a Pompe mouse model, here, we report that the enzymatic defect results in a premature saturating glycogen overload and a high number of enlarged lysosomes...
October 31, 2018: Acta Neuropathologica Communications
Shannon L Risacher, Martin R Farlow, Daniel R Bateman, Francine Epperson, Eileen F Tallman, Rose Richardson, Jill R Murrell, Frederick W Unverzagt, Liana G Apostolova, Jose M Bonnin, Bernardino Ghetti, Andrew J Saykin
This study aimed to determine the pattern of [18 F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [18 F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [18 F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer's disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [18 F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem...
October 29, 2018: Acta Neuropathologica Communications
Urmi Sengupta, Mauro Montalbano, Salome McAllen, Gerard Minuesa, Michael Kharas, Rakez Kayed
Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with structural and functional alterations of brain cells causing progressive deterioration of memory and other cognitive functions. Recent studies demonstrate that several neurodegenerative diseases, including AD exhibit RNA-binding proteins (RBPs) pathologies, including TAR DNA -binding protein (TDP-43), fused in sarcoma (FUS), superoxide dismutase (SOD1) and T-interacting antigen-1 (TIA-1), highlighting the role of RBPs in neurodegeneration...
October 26, 2018: Acta Neuropathologica Communications
Filippo Pinto E Vairo, Nicole Bertsch, Eric W Klee, Ralitza H Gavrilova
No abstract text is available yet for this article.
October 24, 2018: Acta Neuropathologica Communications
Shu-Ting Liu, Shu-Min Zhong, Xue-Yan Li, Feng Gao, Fang Li, Meng-Lu Zhang, Ke Zhu, Xing-Huai Sun, Xin Wang, Yanying Miao, Xiong-Li Yang, Zhongfeng Wang
It was previously shown that EphB/ephrinB reverse signaling in retinal ganglion cells (RGCs) is activated and involved in RGC apoptosis in a rat chronic ocular hypertension (COH) model. In the present work, we first show that ephrinB/EphB forward signaling was activated in COH retinas, and RGC apoptosis in COH retinas was reduced by PP2, an inhibitor of ephrinB/EphB forward signaling. We further demonstrate that treatment of cultured Müller cells with ephrinB1-Fc, an EphB1 activator, or intravitreal injection of ephrinB1-Fc in normal rats induced an increase in phosphorylated EphB levels in these cells, indicating the activation of ephrinB/EphB forward signaling, similar to those in COH retinas...
October 24, 2018: Acta Neuropathologica Communications
Michaela Kerstin Müller, Eric Jacobi, Kenji Sakimura, Roberto Malinow, Jakob von Engelhardt
Amyloid beta (Aβ)-mediated synapse dysfunction and spine loss are considered to be early events in Alzheimer's disease (AD) pathogenesis. N-methyl-D-aspartate receptors (NMDARs) have previously been suggested to play a role for Amyloid beta (Aβ) toxicity. Pharmacological block of NMDAR subunits in cultured neurons and mice suggested that NMDARs containing the GluN2B subunit are necessary for Aβ-mediated changes in synapse number and function in hippocampal neurons. Interestingly, NMDARs undergo a developmental switch from GluN2B- to GluN2A-containing receptors...
October 23, 2018: Acta Neuropathologica Communications
Myriam Vezain, Matthieu Lecuyer, Marina Rubio, Valérie Dupé, Leslie Ratié, Véronique David, Laurent Pasquier, Sylvie Odent, Sophie Coutant, Isabelle Tournier, Laetitia Trestard, Homa Adle-Biassette, Denis Vivien, Thierry Frébourg, Bruno J Gonzalez, Annie Laquerrière, Pascale Saugier-Veber
Extreme microcephaly and rhombencephalosynapsis represent unusual pathological conditions, each of which occurs in isolation or in association with various other cerebral and or extracerebral anomalies. Unlike microcephaly for which several disease-causing genes have been identified with different modes of inheritance, the molecular bases of rhombencephalosynapsis remain unknown and rhombencephalosynapsis presents mainly as a sporadic condition consistent with de novo dominant variations. We report for the first time the association of extreme microcephaly with almost no sulcation and rhombencephalosynapsis in a fœtus for which comparative patient-parent exome sequencing strategy revealed a heterozygous de novo missense variant in the ADGRL2 gene...
October 19, 2018: Acta Neuropathologica Communications
Melanie Hüttenrauch, Isabella Ogorek, Hans Klafki, Markus Otto, Christine Stadelmann, Sascha Weggen, Jens Wiltfang, Oliver Wirths
Alzheimer's disease (AD) is an irreversible, devastating neurodegenerative brain disorder characterized by the loss of neurons and subsequent cognitive decline. Despite considerable progress in the understanding of the pathophysiology of AD, the precise molecular mechanisms that cause the disease remain elusive. By now, there is ample evidence that activated microglia have a critical role in the initiation and progression of AD. The present study describes the identification of Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel AD-related factor in both transgenic mice and sporadic AD patients by expression profiling, immunohistochemistry and ELISA measurements...
October 19, 2018: Acta Neuropathologica Communications
Rachel Jester, Iya Znoyko, Maria Garnovskaya, Joseph N Rozier, Ryan Kegl, Sunil Patel, Tuan Tran, Malak Abedalthagafi, Craig M Horbinski, Mary Richardson, Daynna J Wolff, Razvan Lapadat, William Moore, Fausto J Rodriguez, Jason Mull, Adriana Olar
Endolymphatic sac tumor (ELST) is a rare neoplasm arising in the temporal petrous region thought to originate from endolymphatic sac epithelium. It may arise sporadically or in association with Von-Hippel-Lindau syndrome (VHL). The ELST prevalence in VHL ranges from 3 to 16% and may be the initial presentation of the disease. Onset is usually in the 3rd to 5th decade with hearing loss and an indolent course. ELSTs present as locally destructive lesions with characteristic computed tomography imaging features...
October 19, 2018: Acta Neuropathologica Communications
Masashi Takanashi, Manabu Funayama, Eiji Matsuura, Hiroyo Yoshino, Yuanzhe Li, Sho Tsuyama, Hiroshi Takashima, Kenya Nishioka, Nobutaka Hattori
Leucine-rich repeat kinase 2 (LRRK2) is the most common causative gene for autosomal dominant Parkinson's disease (PD) and is also known to be a susceptibility gene for sporadic PD. Although clinical symptoms with LRRK2 mutations are similar to those in sporadic PD, their pathologies are heterogeneous and include nigral degeneration with abnormal inclusions containing alpha-synuclein, tau, TAR DNA-binding protein 43, and ubiquitin, or pure nigral degeneration with no protein aggregation pathologies. We discovered two families harboring heterozygous and homozygous c...
October 17, 2018: Acta Neuropathologica Communications
Erik A Williams, Julie J Miller, Shilpa S Tummala, Tristan Penson, A John Iafrate, Tareq A Juratli, Daniel P Cahill
TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM). Here, we characterized the subset of IDH-wt GBMs that do not have TERTp mutations. In a cohort of 121 adult grade IV gliomas, we identified 109 IDH-wt GBMs, after excluding 11 IDH-mutant cases and one H3F3A -mutant case. Within the IDH-wt cases, 16 cases (14.7%) were TERTp wild-type (TERTp-wt). None of the 16 had BRAF V600E or H3F3A G34 hotspot mutations. When compared to TERTp mutants, patients with TERTp-wt GBMs, were significantly younger at first diagnosis (53...
October 17, 2018: Acta Neuropathologica Communications
Kelly Ceyzériat, Lucile Ben Haim, Audrey Denizot, Dylan Pommier, Marco Matos, Océane Guillemaud, Marie-Ange Palomares, Laurene Abjean, Fanny Petit, Pauline Gipchtein, Marie-Claude Gaillard, Martine Guillermier, Sueva Bernier, Mylène Gaudin, Gwenaëlle Aurégan, Charlène Joséphine, Nathalie Déchamps, Julien Veran, Valentin Langlais, Karine Cambon, Alexis P Bemelmans, Jan Baijer, Gilles Bonvento, Marc Dhenain, Jean-François Deleuze, Stéphane H R Oliet, Emmanuel Brouillet, Philippe Hantraye, Maria-Angeles Carrillo-de Sauvage, Robert Olaso, Aude Panatier, Carole Escartin
Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer's disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies...
October 16, 2018: Acta Neuropathologica Communications
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