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https://www.readbyqxmd.com/read/29665116/atrophy-and-microglial-distribution-in-primary-progressive-aphasia-with-tdp-43
#1
Garam Kim, Kabriya Bolbolan, Tamar Gefen, Sandra Weintraub, Eileen H Bigio, Emily Rogalski, Marek-Marsel Mesulam, Changiz Geula
OBJECTIVE: To quantitatively determine the density and distribution of activated microglia across cortical regions and hemispheres in the brains of primary progressive aphasia (PPA) participants with pathologic diagnoses of FTLD-TDP, and to examine the relationships between microglial densities, patterns of focal atrophy, TDP-43 inclusions, and clinical phenotype. METHODS: Activated microglia and TDP-43 inclusions were visualized in whole-hemisphere brain sections using immunohistochemical methods from 5 participants with PPA-TDP...
April 17, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29662239/elimination-of-tdp-43-inclusions-linked-to-amyotrophic-lateral-sclerosis-by-a-misfolding-specific-intrabody-with-dual-proteolytic-signals
#2
Yoshitaka Tamaki, Akemi Shodai, Toshifumi Morimura, Ryota Hikiami, Sumio Minamiyama, Takashi Ayaki, Ikuo Tooyama, Yoshiaki Furukawa, Ryosuke Takahashi, Makoto Urushitani
Aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is implicated in the pathogenesis of sporadic and certain familial forms of amyotrophic lateral sclerosis (ALS), suggesting elimination of TDP-43 aggregates as a possible therapeutic strategy. Here we generated and investigated a single-chain variable fragment (scFv) derived from the 3B12A monoclonal antibody (MAb) that recognises D247 of the TDP-43 nuclear export signal, an epitope masked in the physiological state. In transfected HEK293A cells, 3B12A scFv recapitulated the affinity of the full-length MAb to mislocalised TDP-43 with a defective nuclear localising signal and to a TDP-43 inclusion mimic with cysteine-to-serine substitution at RRM1...
April 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29660838/tdp-43-pathology-in-multiple-system-atrophy-colocalization-of-tdp-43-and-%C3%AE-synuclein-in-glial-cytoplasmic-inclusions
#3
Shunsuke Koga, Wen-Lang Lin, Ronald L Walton, Owen A Ross, Dennis 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...
April 16, 2018: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29652933/rhogapp190-a-potential-player-in-tbph-mediated-neurodegeneration-in-drosophila
#4
Simona Langellotti, Giulia Romano, Fabian Feiguin, Francisco Ernesto Baralle, Maurizio Romano
TDP-43 is an ubiquitous and highly conserved ribonucleoprotein involved in several cellular processes including pre-mRNA splicing, transcription, mRNA stability and transport. Notwithstanding the evidence of TDP-43 involvement in the pathogenesis of different neurodegenerative disorders (i.e. ALS and FTLD), the underlying mechanisms are still unclear. Given the high degree of functional similarity between the human and fly orthologs of TDP-43, Drosophila melanogaster is a simple and useful model to study the pathophysiological role of this protein in vivo...
2018: PloS One
https://www.readbyqxmd.com/read/29650702/rna-buffers-the-phase-separation-behavior-of-prion-like-rna-binding-proteins
#5
Shovamayee Maharana, Jie Wang, Dimitrios K Papadopoulos, Doris Richter, Andrey Pozniakovsky, Ina Poser, Marc Bickle, Sandra Rizk, Jordina Guillén-Boixet, Titus Franzmann, Marcus Jahnel, Lara Marrone, Young-Tae Chang, Jared Sterneckert, Pavel Tomancak, Anthony A Hyman, Simon Alberti
Prion-like RNA binding proteins (RBPs) such as TDP-43 or FUS are largely soluble in the nucleus, but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNA critically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells...
April 12, 2018: Science
https://www.readbyqxmd.com/read/29649363/a-targeted-differential-top-down-proteomic-methodology-for-comparison-of-apoa-i-proteoforms-in-individuals-with-high-and-low-hdl-efflux-capacity
#6
Henrique Dos Santos Seckler, Luca Fornelli, R Kannan Mutharasan, C Shad Thaxton, Ryan T Fellers, Martha Daviglus, Allan Sniderman, Daniel Rader, Neil L Kelleher, Donald M Lloyd-Jones, Philip D Compton, John T Wilkins
Top-down proteomics (TDP) allows precise determination/characterization of the different proteoforms derived from the expression of a single gene. In this study, we targeted apolipoprotein A-I (ApoA-I), a mediator of high-density-lipoprotein cholesterol efflux (HDL-E), which is inversely associated with coronary heart disease risk. Absolute ApoA-I concentration and allelic variation only partially explain inter-individual HDL-E variation. Therefore, we hypothesize that differences in HDL-E are associated with the abundances of different ApoA-I proteoforms...
April 12, 2018: Journal of Proteome Research
https://www.readbyqxmd.com/read/29623031/tar-dna-binding-protein-43-loss-of-function-induced-by-phosphorylation-at-s409-410-blocks-autophagic-flux-and-participates-in-secondary-brain-injury-after-intracerebral-hemorrhage
#7
Liang Sun, Kai Zhang, Weiwei Zhai, Haiying Li, Haitao Shen, Zhengquan Yu, Gang Chen
This study aimed to determine the role of TAR DNA binding protein-43 (TDP-43) in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and its underlying mechanisms. After ICH, expression of TDP-43 in the nucleus was significantly decreased, and its expression in the cytoplasm increased both in vivo and in vitro , which indicates that TDP-43 translocates from the nucleus to the cytoplasm during SBI after ICH. In addition, mutations at S409/410 of TDP-43 could inhibit its phosphorylation, attenuate nuclear loss, and abolish the increase in neuronal apoptosis in the subcortex...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29618024/a-novel-long-non-coding-rna-myolinc-regulates-myogenesis-through-tdp-43-and-filip1
#8
Giuseppe Militello, Mohammed Rabiul Hosen, Yuliya Ponomareva, Pascal Gellert, Tyler Weirick, David John, Sajedah Mahmoud Hindi, Kamel Mamchaoui, Vincent Mouly, Claudia Döring, Lidan Zhang, Miki Nakamura, Ashok Kumar, So-Ichiro Fukada, Stefanie Dimmeler, Shizuka Uchida
Myogenesis is a complex process required for skeletal muscle formation during embryonic development and for regeneration and growth of myofibers in adults. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) play key roles in regulating cell fate decision and function in various tissues. However, the role of lncRNAs in the regulation of myogenesis remains poorly understood. In this study, we identified a novel muscle-enriched lncRNA called "Myolinc (AK142388)", which we functionally characterized in the C2C12 myoblast cell line...
April 3, 2018: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29617352/loss-of-iswi-function-in-drosophila-nuclear-bodies-drives-cytoplasmic-redistribution-of-drosophila-tdp-43
#9
Luca Lo Piccolo, Rosa Bonaccorso, Andrea Attardi, Lorenzo Li Greci, Giulia Romano, Martina Sollazzo, Giorgio Giurato, Antonia Maria Rita Ingrassia, Fabian Feiguin, Davide F V Corona, Maria Cristina Onorati
Over the past decade, evidence has identified a link between protein aggregation, RNA biology, and a subset of degenerative diseases. An important feature of these disorders is the cytoplasmic or nuclear aggregation of RNA-binding proteins (RBPs). Redistribution of RBPs, such as the human TAR DNA-binding 43 protein (TDP-43) from the nucleus to cytoplasmic inclusions is a pathological feature of several diseases. Indeed, sporadic and familial forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration share as hallmarks ubiquitin-positive inclusions...
April 4, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29615863/the-d2-dopamine-receptor-interferes-with-the-protective-effect-of-the-a-2a-adenosine-receptor-on-tdp-43-mislocalization-in-experimental-models-of-motor-neuron-degeneration
#10
Chia-You Lai, Yu-Ju Liu, Hsing-Lin Lai, Hui-Mei Chen, Hung-Chi Kuo, Yu-Ping Liao, Yijuang Chern
The A2A adenosine receptor (A2A R) and D2 dopamine receptor (D2 R) are two G-protein-coupled receptors that can form dimers and negatively regulate their partners. TAR DNA-binding protein (TDP-43) is a nuclear protein that has been implicated in amyotrophic lateral sclerosis (ALS). Mislocalization of TDP-43 from the nucleus to the cytoplasm is an early step of TDP-43 proteinopathy. Our previous studies indicated that A2A R is a potential drug target for ALS because treatment with an A2A R agonist (JMF1907; a T1-11 analog) prevents reactive oxygen species (ROS)-induced TDP-43 mislocalization in a motor neuron cell line (NSC34) and delays motor impairment in a TDP-43 transgenic ALS mouse model...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29614661/hippocampal-sclerosis-in-the-oldest-old-a-finnish-population-based-study
#11
Mia Kero, Anna Raunio, Tuomo Polvikoski, Pentti J Tienari, Anders Paetau, Liisa Myllykangas
BACKGROUND: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. OBJECTIVE: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied...
March 28, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29611555/endolysosomal-pathway-activity-protects-cells-from-neurotoxic-tdp-43
#12
COMMENT
Christine Leibiger, Jana Deisel, Andreas Aufschnaiter, Stefanie Ambros, Maria Tereshchenko, Bert M Verheijen, Sabrina Büttner, Ralf J Braun
The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP 43). Using a yeast model for TDP 43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP 43. This clearance occurred via TDP 43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy...
March 21, 2018: Microbial Cell
https://www.readbyqxmd.com/read/29599716/atrophy-in-the-thalamus-but-not-cerebellum-is-specific-for-c9orf72-ftd-and-als-patients-an-atlas-based-volumetric-mri-study
#13
Sonja Schönecker, Christiane Neuhofer, Markus Otto, Albert Ludolph, Jan Kassubek, Bernhard Landwehrmeyer, Sarah Anderl-Straub, Elisa Semler, Janine Diehl-Schmid, Catharina Prix, Christian Vollmar, Juan Fortea, Hans-Jürgen Huppertz, Thomas Arzberger, Dieter Edbauer, Berend Feddersen, Marianne Dieterich, Matthias L Schroeter, Alexander E Volk, Klaus Fließbach, Anja Schneider, Johannes Kornhuber, Manuel Maler, Johannes Prudlo, Holger Jahn, Tobias Boeckh-Behrens, Adrian Danek, Thomas Klopstock, Johannes Levin
Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29587294/macroscopic-localized-subicular-thinning-as-a-potential-indicator-of-amyotrophic-lateral-sclerosis
#14
Hiroki Yamada, Takahiro Takeda, Toshiki Uchihara, Shizuko Sato, Susumu Kirimura, Yuka Hirota, Makoto Kodama, Masanobu Kitagawa, Katsuiku Hirokawa, Takanori Yokota, Shuta Toru
Subicular degeneration occurs in amyotrophic lateral sclerosis (ALS) patients. However, it was unknown whether microscopic subicular degeneration could be observed as macroscopic changes and whether these changes were associated with the transactive-response DNA binding protein 43 kDa (TDP-43) pathology. Topographic differences between subicular degeneration caused by ALS and Alzheimer disease (AD) had also not been characterized. Here we investigated the subiculum and related areas in autopsied brains from 3 ALS and 3 AD patients...
March 23, 2018: European Neurology
https://www.readbyqxmd.com/read/29584904/combined-pathologies-in-ftld-tdp-types-a-and-c
#15
Tamar Gefen, Saman S Ahmadian, Qinwen Mao, Garam Kim, Mustafa Seckin, Borna Bonakdarpour, Eliana Marisa Ramos, Giovanni Coppola, Rosa Rademakers, Emily Rogalski, Alfred Rademaker, Sandra Weintraub, M-Marsel Mesulam, Changiz Geula, Eileen H Bigio
This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLD-TDP type-C cases (12...
March 23, 2018: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29582428/selective-late-sodium-current-inhibitor-gs-458967-suppresses-torsades-de-pointes-by-mostly-affecting-perpetuation-but-not-initiation-of-the-arrhythmia
#16
Alexandre Bossu, Marien J C Houtman, Veronique M F Meijborg, Rosanne Varkevisser, Henriette D M Beekman, Albert Dunnink, Jacques M T de Bakker, Nevena Mollova, Sridharan Rajamani, Luiz Belardinelli, Marcel A G van der Heyden, Marc A Vos
BACKGROUND AND PURPOSE: Enhanced late sodium current (late INa ) in heart failure and long QT syndrome type 3 is proarrhythmic. GS-458967 (GS967) is a selective and potent late INa inhibitor. This study aimed to evaluate the antiarrhythmic effect of late INa inhibition by GS967 in the chronic atrioventricular block (CAVB) dog model sensitive to Torsade de Pointes arrhythmias (TdP) and to elucidate its electrophysiological mode of action in vivo and in vitro. METHODS - RESULTS: GS967 (IC50 for late INa ~ 200 nM) markedly shortened action potential duration of canine ventricular cardiomyocytes and repolarization parameters in vivo in sinus rhythm (SR, n=10) dogs, in a concentration-dependent manner...
March 27, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29581800/impact-of-drug-induced-long-qt-syndrome-a-systematic-review
#17
Karuppiah Arunachalam, Seetha Lakshmanan, Abhishek Maan, Narendra Kumar, Paari Dominic
Background: Drug induced long QT syndrome is quite common in daily clinical practice but its impact is unknown. Methods: PubMed and EMBASE databases (until May 2, 2017) were searched to identify studies reporting drug induced long QT syndrome and followed the PRISMA guidelines. The main outcomes measured in these studies were QTc prolongation, ventricular arrhythmias, torsade de pointes (TdP) and death. Results: Out of 176 non-duplicate reports, 36 studies satisfied inclusion criteria and provided data on patients exposed to drugs that can potentially cause long QT...
May 2018: Journal of Clinical Medicine Research
https://www.readbyqxmd.com/read/29581412/hnrnp-l-represses-cryptic-exons
#18
Sean P McClory, Kristen W Lynch, Jonathan P Ling
The fidelity of RNA splicing is regulated by a network of splicing enhancers and repressors, although the rules that govern this process are not yet fully understood. One mechanism that contributes to splicing fidelity is the repression of nonconserved cryptic exons by splicing factors that recognize dinucleotide repeats. We previously identified that TDP-43 and PTBP1/PTBP2 are capable of repressing cryptic exons utilizing UG and CU repeats, respectively. Here we demonstrate that hnRNP L (HNRNPL) also represses cryptic exons by utilizing exonic CA repeats, particularly near the 5'SS...
March 26, 2018: RNA
https://www.readbyqxmd.com/read/29577934/selective-spatio-temporal-vulnerability-of-central-nervous-system-neurons-to-pathological-tar-dna-binding-protein-43-in-aged-transgenic-mice
#19
Annika van Hummel, Gabriella Chan, Julia van der Hoven, Marco Morsch, Stefania Ippati, Lisa Suh, Mian Bi, Prita R Asih, Wei Siang Lee, Troy A Butler, Magdalena Przybyla, Glenda M Halliday, Olivier Piguet, Matthew C Kiernan, Roger S Chung, Lars M Ittner, Yazi D Ke
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Histopathologically, the majority of ALS cases present with abnormal cytoplasmic accumulation and aggregation of the nuclear RNA-regulating protein TAR DNA-binding protein 43 (TDP-43). Pathogenic mutations in the TARDBP gene that encodes TDP-43 have been identified in familial ALS. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice), presenting with early-onset motor deficits in adolescent animals...
March 22, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29575800/membrane-based-sds-depletion-ahead-of-peptide-and-protein-analysis-by-mass-spectrometry
#20
Nicole Unterlander, Alan A Doucette
SDS interferes with both bottom-up and top-down MS analysis, requiring removal prior to detection. Filter-aided sample prep (FASP) is favored for bottom-up proteomics (BUP) while acetone precipitation is popular for top-down proteomics (TDP). We recently demonstrated acetone precipitation in a membrane filter cartridge. Alternatively, our automated electrophoretic device, termed transmembrane electrophoresis (TME), depletes SDS for both TDP and BUP studies. Here we compare TME to these two alternative methods of SDS depletion in both BUP and TDP workflows...
March 25, 2018: Proteomics
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